Substituted isoquinolinones and quinazolinones

ABSTRACT

The invention relates to substituted nitrogen containing bicyclic heterocycles of the formula (I) 
                         
wherein Z is CH 2  or N—R 4  and X, R 1 , R 2 , R 4 , R 6 , R 7  and n are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of MDM2 and/or MDM4, or variants thereof.

This application claims benefit under 35 U.S.C. §119(e) from U.S.Provisional Application 61/288,992 filed 22 Dec. 2009 and InternationalApplication Serial No. PCT/CN2010/078927 filed 19 Nov. 2010.

The present invention relates to substituted nitrogen containingbicyclic heterocycles, capable of inhibiting the interaction betweenp53, or variants thereof, and MDM2 and/or MDM4, or variants thereof,respectively, especially binding to MDM2 and/or MDM4, or variantsthereof, a process for the preparation of such compounds, pharmaceuticalpreparations comprising such compounds, uses and methods of use for suchcompounds in the treatment (including therapy and/or prophylaxis),and/or related subject matter as specified below. p53 refers to allgenes and/or proteins encoded thereof with the names TP53, p53, TP73,p73, TP63, TP73L, p63. MDM2 refers to all genes and/or proteins encodedthereof with the names MDM2, Mdm2, HDM2, Hdm2. MDM4 refers to all genesand/or proteins encoded thereof with the names MDM4, Mdm4, HDM4, Hdm4,MDMX, MdmX, HDMX, HdmX.

Protein p53 is known as a tumor suppressor protein which helps tocontrol cellular integrity and prevents the proliferation of permanentlydamaged cells by initiating, among other responses, growth arrest orapoptosis (controlled cell death). p53 mediates its effects in that itis a transcription factor capable of regulating a number of genes thatregulate e.g. cell cycle and apoptosis. Thus, p53 is an important cellcycle inhibitor. These activities are tightly controlled by MDM2, animportant negative regulator of the p53 tumor supressor. “MDM2”(originally from the oncogene “murine double minute 2”) refers both tothe name of the gene as well as the protein encoded by that gene. MDM2protein functions both as an E3 ubiquitin ligase that recognizes theN-terminal trans-activation domain (TAD) of the p53 tumor suppressor andthus mediates the ubiquitin-dependent degradation of p53, and as aninhibitor of p53 transcriptional activation.

The original mouse oncogene, which codes for the MDM2 protein, wasoriginally cloned from a transformed mouse cell line. The humanhomologue of this protein was later identified and is sometimes alsocalled HDM2 (for “human double minute 2”). Further supporting the roleof MDM2 as an oncogene, several human tumor and proliferative diseasetypes have been shown to have increased levels of MDM2, including interalia soft tissue sarcomas, bone cancer, e.g. osteosarcomas, breasttumors, bladder cancer, Li-Fraumeni syndrome, brain tumor,rhabdomyosarcoma and adrenocortical carcinoma and the like. Anotherprotein belonging to the MDM2 family is MDM4, also known as MDMX.

Dysregulation of the MDM2/p53 ratio, e.g. due to mutations,polymorphisms or molecular defects in the affected cells, can thus befound in many proliferative diseases. MDM2, in view of its mentionedeffects, is capable to inhibit the activity of the tumor suppressorprotein p53, thus leading to loss of p53's tumor suppressor activity andinhibiting regulatory mechanisms that impede cells from uncontrolledproliferation. As a consequence, uncontrolled proliferation can takeplace, leading to tumors, leukemias or other proliferative diseases.

Thus there is a need for new drugs that are capable to interfere withthe interaction between p53 and MDM2 or especially oncogenic variantsthereof and that thus allow p53 to exert its beneficial effect againstuncontrolled tumor growth, allowing it e.g. to accumulate, to arrest thecell cycle and/or to cause apoptosis of affected cells.

SUMMARY OF THE INVENTION

It has now been found that a novel class of substituted nitrogencontaining bicyclic heterocycles shows potent inhibition of the MDM2/p53interaction (this term including MDM2/p53 interaction and/or MDM4/p53interaction herein, in particular Hdm2/p53 and/or Hdm4/p53 interaction)and the corresponding compounds thus represent a novel type of compoundsthat are useful in the treatment of a number of disorders, such asproliferative diseases. The invention relates therefore to thesecompounds as drugs as well as to the other inventive embodimentsindicated above and below.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates in a first aspect to a compound of formula (I),and/or a tautomer and/or N-oxide and/or a pharmaceutically acceptablesalt and/or solvate thereof,

wherein

Z is CH₂ or N—R⁴;

X is halogen;

R⁴ is selected from the group consisting of

H—

C₁-C₇-alkyl-;

R⁶ is independently selected from the group consisting of

H—

R′O—

(R′)₂N—;

R⁷ is independently selected from the group consisting of

R′O—

(R′)₂N—;

each R′ is independently selected from the group consisting of

H—

C₁-C₇-alkyl-

C₁-C₇-alkenyl-

halo-C₁-C₇-alkyl-

halo-C₁-C₇-alkenyl-

C₃-C₁₂-cycloalkyl-

heterocyclyl-

aryl-

hydroxy-C₁-C₇-alkyl-

C₁-C₇-alkoxy-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-

N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-

heterocyclyl-C₁-C₇-alkyl-

aryl-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-

halo-C₁-C₇-alkyl-carbonyl-

hydroxy-C₁-C₇-alkyl-carbonyl-

C₁-C₇-alkoxy-C₁-C₇-alkyl-carbonyl-

amino-C₁-C₇-alkyl-carbonyl-

N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-

N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-

C₃-C₁₂-cycloalkyl-carbonyl-

heterocyclyl-C₁-C₇-alkyl-carbonyl-

aryl-C₁-C₇-alkyl-carbonyl-

C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-carbonyl-

heterocyclyl-carbonyl-

aryl-carbonyl-

C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

halo-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

hydroxy-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkoxy-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

C₃-C₁₂-cycloalkyl-carbonyl-C₁-C₇-alkyl-

heterocyclyl-carbonyl-C₁-C₇-alkyl-

aryl-carbonyl-C₁-C₇-alkyl-

carbonyl-C₁-C₇-alkyl-

hydroxy-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl-

amino-carbonyl-C₁-C₇-alkyl-

N—C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-

N,N-di-C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-

C₃-C₁₂-cycloalkyl-carbonyl-C₁-C₇-alkyl-

heterocyclyl-carbonyl-C₁-C₇-alkyl-

aryl-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

halo-C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-

halo-C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

-   -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are        unsubstituted or substituted by 1-4 substituents selected from        C₁-C₇-alkyl, halo-C₁-C₇-alkyl, halogen, hydroxy, C₁-C₇-alkoxy,        amino, nitro or cyano;

each R¹ is independently selected from the group consisting of

halogen-

cyano-

nitro-

C₁-C₇-alkenyl-

halo-C₁-C₇-alkyl-

hydroxy-

C₁-C₇-alkoxy-

amino-

N—C₁-C₇-alkyl-amino-

amino-carbonyl-amino-

N—C₁-C₇-alkyl-amino-carbonyl-amino-

N,N-di-C₁-C₇-alkyl-amino-carbonyl-amino-

C₁-C₇-alkyl-carbonyl-amino-

amino-carbonyl-

N—C₁-C₇-alkyl-amino-carbonyl-

N,N-di-C₁-C₇-alkyl-amino-carbonyl-

hydroxy-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-

N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-;

n is 0, 1 or 2;

R² is selected from

-   -   (A) phenyl, 2-pyridyl or 3-pyridyl        -   said phenyl, 2-pyridyl or 3-pyridyl being substituted in            para-position (relative to the isoquinolinone or            quinazolinone), by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   -   and said phenyl, 2-pyridyl or 3-pyridyl being optionally            substituted by 1-2 additional substituents selected from        -   halogen-        -   cyano-        -   halo-C₁-C₇-alkyl-        -   hydroxy-        -   C₁-C₇-alkoxy-        -   hydroxy-C₁-C₇-alkyl-;            or

    -   (B) phenyl, 2-pyridyl or 3-pyridyl        -   said phenyl, 2-pyridyl or 3-pyridyl being substituted in            para-position (relative to the isoquinolinone or            quinazolinone), by a substituent selected from        -   cyano-        -   halogen-        -   nitro-        -   halo-C₁-C₇-alkyl-        -   hydroxy-C₁-C₇-alkyl-        -   hydroxy-carbonyl-        -   C₁-C₇-alkoxy-carbonyl-        -   C₁-C₇-alkyl-carbonyl-        -   C₁-C₇-alkoxy-        -   (C-bound)-heterocyclyl-            -   wherein (C-bound)-heterocyclyl is unsubstituted or                substituted by 1-4 substituents selected from                C₁-C₇-alkyl, halo-C₁-C₇-alkyl, halogen, hydroxy,                C₁-C₇-alkoxy, amino, nitro or cyano;        -   and wherein said phenyl, 2-pyridyl and 3-pyridyl are            optionally substituted by 1-2 additional substituents            independently selected from        -   halogen-        -   cyano-        -   halo-C₁-C₇-alkyl-        -   hydroxy-        -   C₁-C₇-alkoxy-        -   (C-bound or N-bound)heterocyclyl-C₁-C₄-alkyl- and        -   hydroxy-C₁-C₇-alkyl-;            or

    -   (C) phenyl,        -   substituted in ortho-position (relative to the            isoquinolinone or quinazolinone), by            R³O—            -   and substituted in para- or meta-position by a                substituent selected from methyl, chloro,                C₁-C₇-alkyl-carbonyl- or C₁-C₇-alkoxy-carbonyl-;

    -   (D) (C-bound)-heterocycle selected from

-   -   -   wherein Z is a 4-6 membered heterocyclic ring, annulated to            phenyl in para and meta position, containing 1-3 heteroatoms            selected from N, O or S,        -   which is optionally substituted by 1-2 additional            substituents selected from        -   halogen-        -   cyano-        -   C₁-C₇-alkyl-        -   halo-C₁-C₇-alkyl-        -   hydroxy-        -   C₁-C₇-alkoxy-        -   hydroxy-C₁-C₇-alkyl-;

    -   (E) pyrazin-2-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 5 position by:

-   -   (F) pyridazin-3-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 6 position by:

-   -   or    -   (G) pyrimidin-2-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 5 position by:

wherein each R³ is independently selected from

-   -   H—    -   C₁-C₇-alkyl-    -   hydroxy-C₁-C₇-alkyl-    -   C₃-C₁₂-cycloalkyl-    -   C₁-C₇-alkoxy-C₁-C₇-alkyl-carbonyl-    -   amino-C₁-C₇-alkyl-carbonyl    -   N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl    -   N,N-di C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl    -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-    -   (R⁵)₂N—C₁-C₇-alkyl-    -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-carbonyl-    -   R⁵O—C₃-C₁₂-cycloalkyl-    -   R⁵O—C₁-C₇-alkyl-    -   R⁵O—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   R⁵O—(C₁-C₇-alkyl)-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   R⁵O—(hydroxy-C₁-C₇-alkyl)-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   (R⁵)₂N—CO—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   C₁-C₇-alkoxycarbonyl-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   hydroxycarbonyl-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   amino-carbonyl-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   R⁵O—C₃-C₁₂-cycloalkyl-carbonyl-    -   (R⁵)₂N-carbonyl-C₁-C₇-alkyl-    -   R⁵O-carbonyl-C₁-C₇-alkyl-    -   aryl-C₁-C₇-alkyl-    -   heterocyclyl-C₁-C₇-alkyl-    -   C₁-C₇-alkyl-carbonyl-    -   halo-C₁-C₇-alkyl-carbonyl-    -   heterocyclyl-carbonyl-    -   aryl-carbonyl-    -   C₃-C₁₂-cycloalkyl-carbonyl-    -   C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   heterocyclyl-    -   aryl-        -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are            unsubstituted or substituted by 1-4 substituents selected            from        -   halogen-        -   C₁-C₇-alkyl-        -   halo-C₁-C₇-alkyl-        -   C₁-C₇-alkyl-carbonyl-        -   C₃-C₁₂-cycloalkyl-carbonyl-        -   C₁-C₇-alkyl-sulfonyl-        -   amino-sulfonyl-        -   N—C₁-C₇-alkyl-amino-sulfonyl-        -   N,N-di-C₁-C₇-alkyl-amino-sulfonyl-        -   amino-carbonyl-        -   N—C₁-C₇-alkyl-amino-carbonyl-        -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-        -   oxo=    -   or    -   two R³, together with the N to which they are attached my form a        3-9 membered heterocyclic ring, optionally containing 1-4        additional heteroatoms selected from N, O or S, said        heterocyclic ring is unsubstituted or substituted by 1-3        substituents selected from:    -   halogen-    -   hydroxy-C₁-C₇-alkyl-    -   C₁-C₇-alkyl-    -   halo-C₁-C₇-alkyl-    -   oxo=    -   hydroxy-    -   C₁-C₇-alkoxy-    -   amino-    -   N—C₁-C₇-alkyl-amino-    -   N,N-di-C₁-C₇-alkyl-amino-    -   hydroxy-carbonyl-    -   C₁-C₇-alkoxy-carbonyl-    -   amino-carbonyl-    -   N—C₁-C₇-alkyl-amino-carbonyl-    -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-    -   C₁-C₇-alkyl-carbonyl-    -   C₁-C₇-alkyl-sulphonyl-    -   heterocyclyl-    -   C₁-C₇-alkyl-carbonyl-amino-    -   C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-;    -   and        each R⁵ is independently selected from:    -   H—    -   hydroxy-C₁-C₇-alkyl-    -   C₁-C₇-alkyl-carbonyl-    -   C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl-    -   amino-carbonyl-C₁-C₇-alkyl-    -   N—C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-    -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-    -   C₁-C₇-alkyl-sulfonyl-    -   amino-sulfonyl-    -   N—C₁-C₇-alkyl-amino-sulfonyl-    -   N,N-di-C₁-C₇-alkyl-amino-sulfonyl-    -   heterocyclyl-carbonyl-    -   amino-carbonyl-    -   N—C₁-C₇-alkyl-amino-carbonyl-    -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-    -   C₃-C₁₂-cycloalkyl-carbonyl-    -   C₁-C₇-alkoxy-carbonyl-amino-C₁-C₇-alkyl-    -   C₁-C₇-alkoxy-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-    -   C₁-C₇-alkoxy-carbonyl-    -   C₃-C₁₂-cycloalkyl-    -   hydroxy-C₃-C₁₂-cycloalkyl-    -   or    -   two R⁵, together with the N to which they are attached may form        a 3, 4, 5, 6, 7, 8 or 9 membered heterocyclic ring, optionally        containing 1, 2, 3 or 4 additional heteroatoms selected from N,        O or S, said heterocyclic ring is unsubstituted or substituted        by from 1 to 3 substituents independently selected from        C₁-C₇-alkyl-    -   oxo=,    -   C₁-C₇-alkyl-carbonyl,    -   C₁-C₇-alkyl-sulphonyl,    -   hydroxy-C₁-C₇-alkyl;    -   with the proviso that if Z is CH₂, n is 0 or 1, and when        present, R¹ is ortho-chloro,    -   and R² is selected from    -   para-C₁-C₃-alkyl-phenyl-    -   para-(halo-C₁-C₃-alkyl)-phenyl-    -   para-C₁-C₃-alkoxy-phenyl-    -   para-halo-phenyl-    -   para-nitro-phenyl-    -   para-(C₁-C₃-alkoxy-carbonyl)-phenyl-    -   para-(hydroxy-carbonyl)-phenyl-    -   wherein the phenyl is optionally substituted by 1-2 additional        substituents, said substituents being independently selected        from halo and methyl, then R⁶ and R⁷ are not both ethoxy or        methoxy.

Wherever a compound or compounds of the formula (I) are mentioned, thisis further also intended to include N-oxides of such compounds,tautomers thereof, and/or a (preferably pharmaceutically acceptable)salt thereof.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, “formula (I)” also means “formula I”. These terms areused interchangeably.

As used herein, the term “alkyl” refers to a fully saturated branched,including single or multiple branching, or unbranched hydrocarbon moietyhaving up to 20 carbon atoms. Unless otherwise provided, alkyl refers tohydrocarbon moieties having 1 to 16 carbon atoms, 1 to 10 carbon atoms,1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.Typically, alkyl groups have 1-7, more preferably 1-4 carbons.

As used herein, the term “alkenyl” refers to a branched, includingsingle or multiple branching, or unbranched hydrocarbon moiety having upto 20 carbon atoms containing at least one carbon carbon double bond.Unless otherwise provided, alkenyl refers to hydrocarbon moieties having2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 7 carbon atoms, or 2 to4 carbon atoms. Representative examples of alkyl include, but are notlimited to ethenyl, propenyl, propenylene, allyl, and 1,4-butadienyl.

As used herein, the term “halo-alkyl” refers to an alkyl as definedherein, that is substituted by one or more halogen groups as definedherein. The halo-alkyl can be mono-halo-alkyl, di-halo-alkyl orpoly-halo-alkyl including per-halo-alkyl. A mono-halo-alkyl can have oneiodo, bromo, chloro or fluoro within the alkyl group. Di-halo-alkyl andpoly-halo-alkyl groups can have two or more of the same halo atoms or acombination of different halo groups within the alkyl. Typically thepoly-halo-alkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2halo groups. Non-limiting examples of halo-alkyl include fluoro-methyl,di-fluoro-methyl, tri-fluoro-methyl, chloro-methyl, di-chloro-methyl,tri-chloro-methyl, penta-fluoro-ethyl, hepta-fluoro-propyl,di-fluoro-chloro-methyl, di-chloro-fluoro-methyl, di-fluoro-ethyl,di-fluoro-propyl, di-chloro-ethyl and dichloro-propyl. A per-halo-alkylrefers to an alkyl having all hydrogen atoms replaced with halogenatoms.

As used herein, unless otherwise specified, the term “hydroxyalkyl”, or“hydroxyethyl”, “hydroxypropyl” etc, refers to an alkyl as defined, thatis substituted by one or more, preferably one, hydroxy groups.

As used herein, the term “halogen” (or “halo”) refers to iodo, bromo,chloro or fluoro. In the context of X, halogen is preferably chloro orbromo, more preferably chloro. In the context of (B), halogen as asubstituent on phenyl, 2-pyridyl or 3-pyridyl is preferably iodo.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Typically, alkoxy groups have 1-7, more preferably 1-4carbons.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated, monocyclic, fused polycyclic, or spiro polycyclic, carbocyclehaving from 3 to 12 ring atoms per carbocycle. Unless otherwiseprovided, cycloalkyl refers to cyclic hydrocarbon groups having between3 and 10 ring carbon atoms or between 3 and 7 ring carbon atoms. Theterm cycloalkyl excludes “aryl”. Exemplary monocyclic hydrocarbon groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl and cyclohexenyl. Exemplary bicyclichydrocarbon groups include octahydroindyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl. Exemplary tricyclic hydrocarbon groups includeadamantyl. As used herein, the term “cycloalkyl” preferably refers tocyclopropyl, cyclopentyl or cyclohexyl.

The term “aryl” refers to an aromatic hydrocarbon group having 6-20carbon atoms in the ring portion. Typically, aryl is monocyclic,bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, theterm “aryl” as used herein, refers to an aromatic substituent which canbe a single aromatic ring, or multiple aromatic rings that are fusedtogether. Non-limiting examples include phenyl or naphthyl. As usedherein, the term “aryl” preferably refers to phenyl.

As used herein, the term “heterocyclyl” or “heterocyclic” refers to aunsaturated (carrying the highest possible number of conjugated doublebonds in the ring(s), then also called heteroaryl), saturated (then alsocalled saturated heterocyclyl) or partially saturated ring or ringsystem, for example a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-,10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or15-membered tricyclic ring system and contains at least one heteroatomselected from N, O and S, where the N and S can also optionally beoxidized to various oxidation states. The heterocyclic group can beattached at a heteroatom or a carbon atom. The heterocyclyl can includefused or bridged rings as well as spirocyclic rings.

In one embodiment herein, heterocyclyl means an unsaturated, saturated,or partially saturated ring or ring system comprising 3, 4, 5, 6, 7, 8,9, 10, 11 or 12 ring atoms, and containing at least one heteroatomselected from N, O and S, where the N and S can also optionally beoxidized, and wherein, unless otherwise stated, the heterocyclic groupcan be attached at a heteroatom or a carbon atom. In one embodiment,heterocyclyl may contain 1, 2, 3 or 4 N atoms, and/or 1 S atom and/orone O atom.

Examples of heterocycles include oxiranyl, azirinyl, aziridinyl,1,2-oxathiolanyl, thienyl, furanyl, tetrahydrofuryl, pyranyl,thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl,benzoisoxazolyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl,pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl,pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl,piperidinyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl,indolizinyl, azepanyl, diazepanyl, especially 1,4-diazepanyl,isoindolyl, 3H-indolyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,cumaryl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl,decahydroquinolyl, octahydroisoquinolyl, dibenzofuranyl,benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl,quinoxalyl (=quinoxalinyl), quinazolinyl, quinazolinyl, cinnolinyl,pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl,phenoxazinyl, chromenyl, isochromenyl, chromanyl, benzo[1,3]dioxol-5-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl, thiochromenyl and isothiochromenyl.

In the context of R′, the term “heterocyclyl-” refers preferably to 5 to6-membered monocyclic unsaturated, partially saturated or saturated ringsystems. Examples include, but are not limited to pyridyl,imidazolidinyl, pyrrolindiyl, pyrimindinyl, piperazinyl, piperidinyl,thiomorpholinyl and morpholinyl.

In the context of (B), the term “(C-bound)-heterocyclyl-” referspreferably to 5- to 6-membered monocyclic unsaturated or partiallysaturated ring systems. Examples include, but are not limited topyrazolyl, imidazole, triazole and tetrazole.

In the context of (D), the term “(C-bound)-heterocyclyl-” referspreferably to 9- to 11-membered bicyclic unsaturated or partiallysaturated ring systems. Examples include, but are not limited toindazolyl, indolyl, benzoisoxazolyl, benzofuranyl and benzothiophenyl.

In the context of R³, the term “heterocyclyl-” refers preferably to 5 to6-membered monocyclic unsaturated, partially saturated or saturated ringsystems. Examples include, but are not limited to pyridyl, pyrimindinyl,piperazinyl, piperidinyl, pyrrolindiyl, imidazolyl, imidazolidinyl,furanyl, tetrazolyl, tetrahydrofuranyl, thienyl, oxazolyl,thiomorpholinyl and morpholinyl.

In the context of R³, where two R³, together with the N to which theyare attached may form a 3-9 membered heterocyclic ring, the term“heterocyclyl-” refers preferably to 4, 5 or 6-membered monocyclicunsaturated, partially saturated or saturated ring systems. Examplesinclude, but are not limited to azetidinyl, pyrazolyl, piperazinyl,piperidinyl, pyrrolindiyl, imidazolidinyl, imidazolyl, furanyl,tetrahydrofuranyl, thienyl, oxazolyl, thiomorpholinyl and morpholinyl.

In the context of R⁵, where two R⁵, together with the N to which theyare attached may form a 3-9 membered heterocyclic ring, the term“heterocyclyl-” refers preferably to 5, 6 or 7-membered monocyclicpartially saturated or saturated ring systems. Examples include, but arenot limited to, piperazinyl, piperidinyl, pyrrolindiyl, imidazolidinyl,thiomorpholinyl, morpholinyl and di-azepanyl.

As used herein, the term “oxy” refers to an —O— linking group.

As used herein, all substituents are written in a way to show the orderof functional groups (groups) they are composed of. The functionalgroups are defined herein above. The point of their attachment isindicated with a hyphen (-), wherein said hyphen indicates a singlebond, or an equal sign (=), wherein said equal sign indicates a doublebond, as appropriate.

“C-bound” means attached via a carbon atom, for example in(C-bound)-heterocyclyl-.

“N-bound” means attached via a nitrogen atom, for example in(N-bound)-heterocyclyl-.

Unless otherwise indicated herein, * indicates a point of attachment

As used herein, the term “protected hydroxy” refers to a hydroxyfunctionality bearing a “protecting group”. Within the scope of thistext, only a readily removable group that is not a constituent of theparticular desired end product of the compounds of the present inventionis designated a “protecting group”, unless the context indicatesotherwise; e.g. a protecting group can be part of a compound of theformula (I), if specifically mentioned. The protection of functionalgroups by such protecting groups, the protecting groups themselves, andtheir cleavage reactions are described for example in standard referenceworks, such as J. F. W. McOmie, “Protective Groups in OrganicChemistry”, Plenum Press, London and New York 1973, in T. W. Greene andP. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition,Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross andJ. Meienhofer), Academic Press, London and New York 1981, in “Methodender organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4thedition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H. Jeschkeit, “Aminosäuren, Peptide, Proteine” (Amino acids,Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharideand Derivate” (Chemistry of Carbohydrates: Monosaccharides andDerivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic ofprotecting groups is that they can be removed readily (i.e. without theoccurrence of undesired secondary reactions) for example by solvolysis,reduction, photolysis or alternatively under physiological conditions(e.g. by enzymatic cleavage).

The term “and/or an N-oxide thereof, a tautomer thereof and/or a(preferably pharmaceutically acceptable) salt thereof” especially meansthat a compound of the formula (I) may be present as such or in mixturewith its N-oxide, as tautomer (e.g. due to keto-enol, lactam-lactim,amide-imidic acid or enamine-imine tautomerism) or in (e.g. equivalencyreaction caused) mixture with its tautomer, or as a salt of the compoundof the formula (I) and/or any of these forms or mixtures of two or moreof such forms.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

In another embodiment there is provided a compound of formula (I) asdescribed herein with the proviso that the compound of formula (I) isnot:

In another embodiment, there is provided a compound of formula (I),and/or a tautomer and/or N-oxide and/or a pharmaceutically acceptablesalt and/or solvate thereof,

wherein

Z is CH₂ or N—R⁴;

X is halogen;

R⁴ is selected from the group consisting of

H—

C₁-C₄-alkyl-;

R⁶ is independently selected from the group consisting of

H—

R′O—

(R′)₂N—;

R⁷ is independently selected from the group consisting of

R′O—

(R′)₂N—;

each R′ is independently selected from the group consisting of

H—

C₁-C₆-alkyl-

C₁-C₆-alkenyl-

halo-C₁-C₄-alkyl-

halo-C₁-C₄-alkenyl-

C₃-C₇-cycloalkyl-

heterocyclyl-

aryl-

hydroxy-C₁-C₄-alkyl-

C₁-C₄-alkoxy-C₁-C₄-alkyl-

amino-C₁-C₄-alkyl-

N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

C₃-C₇-cycloalkyl-C₁-C₄-alkyl-

heterocyclyl-C₁-C₄-alkyl-

aryl-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-

halo-C₁-C₄-alkyl-carbonyl-

hydroxy-C₁-C₄-alkyl-carbonyl-

C₁-C₄-alkoxy-C₁-C₄-alkyl-carbonyl-

amino-C₁-C₄-alkyl-carbonyl-

N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl-

N,N-di-C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl-

C₃-C₇-cycloalkyl-carbonyl-

heterocyclyl-C₁-C₄-alkyl-carbonyl-

aryl-C₁-C₄-alkyl-carbonyl-

C₃-C₇-cycloalkyl-C₁-C₄-alkyl-carbonyl-

heterocyclyl-carbonyl-

aryl-carbonyl-

C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

hydroxy-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

C₁-C₄-alkoxy-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

amino-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

C₃-C₇-cycloalkyl-carbonyl-C₁-C₄-alkyl-

heterocyclyl-carbonyl-C₁-C₄-alkyl-

aryl-carbonyl-C₁-C₄-alkyl-

carbonyl-C₁-C₄-alkyl-

hydroxy-carbonyl-C₁-C₄-alkyl-

C₁-C₄-alkoxy-carbonyl-C₁-C₄-alkyl-

amino-carbonyl-C₁-C₄-alkyl-

N—C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-

C₃-C₇-cycloalkyl-carbonyl-C₁-C₄-alkyl-

heterocyclyl-carbonyl-C₁-C₄-alkyl-

aryl-carbonyl-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-amino-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

halo-C₁-C₄-alkyl-carbonyl-amino-C₁-C₄-alkyl-

halo-C₁-C₄-alkyl-carbonyl-N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

-   -   wherein aryl, heterocyclyl and C₃-C₇-cycloalkyl are        unsubstituted or substituted by 1-4 substituents selected from        C₁-C₄-alkyl, halo-C₁-C₄-alkyl, halogen, hydroxy, C₁-C₄-alkoxy,        amino, nitro or cyano;

each R¹ is independently selected from the group consisting of

halogen-

cyano-

nitro-

C₁-C₄-alkyl-

C₁-C₄-alkenyl-

halo-C₁-C₄-alkyl-

hydroxy-

C₁-C₄-alkoxy-

amino-

N—C₁-C₄-alkyl-amino-

amino-carbonyl-amino-

N—C₁-C₄-alkyl-amino-carbonyl-amino-

N,N-di-C₁-C₄-alkyl-amino-carbonyl-amino-

C₁-C₄ alkyl-carbonyl-amino-

amino-carbonyl-

N—C₁-C₄-alkyl-amino-carbonyl-

N,N-di-C₁-C₄-alkyl-amino-carbonyl-

hydroxy-C₁-C₄-alkyl-

amino-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-amino-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-;

n is 0, 1 or 2;

R² is selected from

-   -   (A) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   C₁-C₄-alkyl-        -   halo-C₁-C₄-alkyl-        -   hydroxy-        -   C₁-C₄-alkoxy-        -   hydroxy-C₁-C₄-alkyl-;            or

    -   (B) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by a substituent selected from        -   cyano-        -   halogen-        -   nitro-        -   C₁-C₄-alkyl-        -   hydroxy-C₁-C₄-alkyl-        -   hydroxy-carbonyl-        -   C₁-C₄-alkoxy-carbonyl-        -   C₁-C₄-alkyl-carbonyl-        -   C₁-C₄-alkoxy-        -   (C-bound)-heterocyclyl-            -   wherein (C-bound)-heterocyclyl is unsubstituted or                substituted by 1-4 substituents selected from                C₁-C₄-alkyl, halo-C₁-C₄-alkyl, halogen, hydroxy,                C₁-C₄-alkoxy, amino, nitro or cyano;        -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   C₁-C₄-alkyl-        -   hydroxy-        -   C₁-C₄-alkoxy-        -   (C-bound or N-bound)heterocyclyl-C₁-C₄-alkyl-        -   hydroxy-C₁-C₄-alkyl-;            or

    -   (C) phenyl,        -   substituted in ortho-position by            R³O—            -   and substituted in para- or meta-position by a                substituent selected from methyl, chloro,                C₁-C₄-alkyl-carbonyl- or C₁-C₄-alkoxy-carbonyl-;

    -   (D) (C-bound)-heterocycle selected from

-   -   -   wherein Z is a 4-6 membered heterocyclic ring, annulated to            phenyl in para and meta position, containing 1-3 heteroatoms            selected from N, O or S,        -   which is optionally substituted by 1-2 additional            substituents selected from        -   halogen-        -   cyano-        -   C₁-C₄-alkyl-        -   halo-C₁-C₄-alkyl-        -   hydroxy-        -   C₁-C₄-alkoxy-        -   hydroxy-C₁-C₄-alkyl-;

    -   (E) pyrazin-2-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 5 position by:

-   -   (F) pyridazin-3-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 6 position by:

-   -   or    -   (G) pyrimidin-2-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 5 position by:

wherein each R³ is independently selected from

-   -   H—    -   C₁-C₄-alkyl-    -   hydroxy-C₁-C₄-alkyl-    -   C₃-C₇-cycloalkyl-    -   C₁-C₄-alkoxy-C₁-C₄-alkyl-carbonyl-    -   amino-C₁-C₄-alkyl-carbonyl    -   N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl    -   N,N-di C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl    -   (R⁵)₂N—C₃-C₇-cycloalkyl-    -   (R⁵)₂N—C₁-C₄-alkyl-    -   (R⁵)₂N—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   (R⁵)₂N—C₃-C₇-cycloalkyl-carbonyl-    -   R⁵O—C₃-C₇-cycloalkyl-    -   R⁵O—C₁-C₄-alkyl-    -   R⁵O—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   R⁵O—(C₁-C₄-alkyl)-C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   R⁵O—(hydroxy-C₁-C₄-alkyl)-C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   (R⁵)₂N—CO—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   C₁-C₄-alkoxycarbonyl-C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   hydroxycarbonyl-C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   amino-carbonyl-C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   R⁵O—C₃-C₇-cycloalkyl-carbonyl-    -   (R⁵)₂N-carbonyl-C₁-C₄-alkyl-    -   R⁵O-carbonyl-C₁-C₄-alkyl-    -   aryl-C₁-C₄-alkyl-    -   heterocyclyl-C₁-C₄-alkyl-    -   C₁-C₄-alkyl-carbonyl-    -   halo-C₁-C₄-alkyl-carbonyl-    -   heterocyclyl-carbonyl-    -   aryl-carbonyl-    -   C₃-C₇-cycloalkyl-carbonyl-    -   C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   heterocyclyl-    -   aryl-        -   wherein aryl, heterocyclyl and C₃-C₇-cycloalkyl are            unsubstituted or substituted by 1-4 substituents selected            from        -   halogen-        -   C₁-C₄-alkyl-        -   halo-C₁-C₄-alkyl-        -   C₁-C₄-alkyl-carbonyl-        -   C₃-C₇-cycloalkyl-carbonyl-        -   C₁-C₄-alkyl-sulfonyl-        -   amino-sulfonyl-        -   N—C₁-C₄-alkyl-amino-sulfonyl-        -   N,N-di-C₁-C₄-alkyl-amino-sulfonyl-        -   amino-carbonyl-        -   N—C₁-C₄-alkyl-amino-carbonyl-        -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-        -   oxo=    -   or    -   two R³, together with the N to which they are attached my form a        3, 4, 5, 6 or 7 membered heterocyclic ring, optionally        containing 1, 2, 3 or 4 additional N heteroatoms and optionally        containing a O atom and/or a S atom, said heterocyclic ring        being unsubstituted or substituted by 1, 2 or 3 substituents        selected from:    -   halogen-    -   hydroxy-C₁-C₄-alkyl-    -   C₁-C₄-alkyl-    -   halo-C₁-C₄-alkyl-    -   oxo=    -   hydroxy-    -   C₁-C₄-alkoxy-    -   amino-    -   N—C₁-C₄-alkyl-amino-    -   N,N-di-C₁-C₄-alkyl-amino-    -   hydroxy-carbonyl-    -   C₁-C₄-alkoxy-carbonyl-    -   amino-carbonyl-    -   N—C₁-C₄-alkyl-amino-carbonyl-    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-    -   C₁-C₄-alkyl-carbonyl-    -   C₁-C₄-alkyl-sulphonyl-    -   heterocyclyl-    -   C₁-C₄-alkyl-carbonyl-amino-    -   C₁-C₄-alkyl-carbonyl-N—C₁-C₄-alkyl-amino-;    -   and        each R⁵ is independently selected from:    -   H—    -   C₁-C₄-alkyl-    -   hydroxy-C₁-C₄-alkyl-    -   C₁-C₄-alkyl-carbonyl-    -   C₁-C₄-alkoxy-carbonyl-C₁-C₄-alkyl-    -   amino-carbonyl-C₁-C₄-alkyl-    -   N—C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-    -   C₁-C₄-alkyl-sulfonyl-    -   amino-sulfonyl-    -   N—C₁-C₄-alkyl-amino-sulfonyl-    -   N,N-di-C₁-C₄-alkyl-amino-sulfonyl-    -   heterocyclyl-carbonyl-    -   amino-carbonyl-    -   N—C₁-C₄-alkyl-amino-carbonyl-    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-    -   C₃-C₇-cycloalkyl-carbonyl-    -   C₁-C₄-alkoxy-carbonyl-amino-C₁-C₄-alkyl-    -   C₁-C₄-alkoxy-carbonyl-N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-    -   C₁-C₄-alkoxy-carbonyl-    -   C₃-C₇-cycloalkyl-    -   hydroxy-C₃-C₇-cycloalkyl-    -   or    -   two R⁵, together with the N to which they are attached may form        a 3, 4, 5, 6 or 7 membered heterocyclic ring, optionally        containing 1, 2, 3 or 4 additional N heteroatoms and/or        optionally containing a O atom and/or a S atom, said        heterocyclic ring being unsubstituted or substituted by from 1,        2 or 3 substituents independently selected from    -   C₁-C₄-alkyl-    -   oxo=,    -   C₁-C₄-alkyl-carbonyl,    -   C₁-C₄-alkyl-sulphonyl,    -   hydroxy-C₁-C₄-alkyl;    -   with the proviso that if Z is CH₂, n is 0 or 1, and when        present, R¹ is ortho-chloro,    -   and R² is selected from    -   para-C₁-C₃-alkyl-phenyl-    -   para-(halo-C₁-C₃-alkyl)-phenyl-    -   para-C₁-C₃-alkoxy-phenyl-    -   para-halo-phenyl-    -   para-nitro-phenyl-    -   para-(C₁-C₃-alkoxy-carbonyl)-phenyl-    -   para-(hydroxy-carbonyl)-phenyl-    -   wherein the phenyl is optionally substituted by 1-2 additional        substituents, said substituents being independently selected        from halo and methyl, then R⁶ and R⁷ are not both ethoxy or        methoxy.

In another embodiment, the invention relates to a compound of formula(I), and/or a tautomer and/or N-oxide and/or a pharmaceuticallyacceptable salt and/or solvate thereof,

wherein

Z is CH₂ or N—R⁴;

X is halogen;

R⁴ is selected from the group consisting of

H—

C₁-C₇-alkyl-;

R⁶ is independently selected from the group consisting of

H—

R′O—

(R)₂N—;

R⁷ is independently selected from the group consisting of

R′O—

(R)₂N—;

R′ is selected from the group consisting of

H—

C₁-C₇-alkenyl-

halo-C₁-C₇-alkyl-

halo-C₁-C₇-alkenyl-

C₃-C₁₂-cycloalkyl-

heterocyclyl-

aryl-

hydroxy-C₁-C₇-alkyl-

C₁-C₇-alkoxy-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-

N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-

heterocyclyl-C₁-C₇-alkyl-

aryl-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-

halo-C₁-C₇-alkyl-carbonyl-

hydroxy-C₁-C₇-alkyl-carbonyl-

C₁-C₇-alkoxy-C₁-C₇-alkyl-carbonyl-

amino-C₁-C₇-alkyl-carbonyl-

N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-

N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-

C₃-C₁₂-cycloalkyl-carbonyl-

heterocyclyl-C₁-C₇-alkyl-carbonyl-

aryl-C₁-C₇-alkyl-carbonyl-

C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-carbonyl-

heterocyclyl-carbonyl-

aryl-carbonyl-

C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

halo-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

hydroxy-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkoxy-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

C₃-C₁₂-cycloalkyl-carbonyl-C₁-C₇-alkyl-

heterocyclyl-carbonyl-C₁-C₇-alkyl-

aryl-carbonyl-C₁-C₇-alkyl-

carbonyl-C₁-C₇-alkyl-

hydroxy-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl-

amino-carbonyl-C₁-C₇-alkyl-

N—C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-

N,N-di-C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-

C₃-C₁₂-cycloalkyl-carbonyl-C₁-C₇-alkyl-

heterocyclyl-carbonyl-C₁-C₇-alkyl-

aryl-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

halo-C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-

halo-C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

-   -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are        unsubstituted or substituted by 1-4 substituents selected from        C₁-C₇-alkyl, halo-C₁-C₇-alkyl, halogen, hydroxy, C₁-C₇-alkoxy,        amino, nitro or cyano;

R¹ is selected from the group consisting of

halogen-

cyano-

nitro-

C₁-C₇-alkenyl-

halo-C₁-C₇-alkyl-

hydroxy-

C₁-C₇-alkoxy-

amino-

N—C₁-C₇-alkyl-amino-

N,N-di-C₁-C₇-alkyl-amino-

hydroxy-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-;

n is 0 to 2;

R² is selected from

-   -   (A) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   halo-C₁-C₇-alkyl-        -   hydroxy-        -   C₁-C₇-alkoxy-        -   hydroxy-C₁-C₇-alkyl-;            or

    -   (B) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by a substituent selected from        -   cyano-        -   halogen-        -   nitro-        -   C₁-C₇-alkyl-        -   halo-C₁-C₇-alkyl-        -   hydroxy-C₁-C₇-alkyl-        -   hydroxy-carbonyl-        -   C₁-C₇-alkoxy-carbonyl-        -   C₁-C₇-alkyl-carbonyl-        -   C₁-C₇-alkoxy-        -   (C-bound)-heterocyclyl-            -   wherein (C-bound)-heterocyclyl is unsubstituted or                substituted by 1-4 substituents selected from                C₁-C₇-alkyl, halo-C₁-C₇-alkyl, halogen, hydroxy,                C₁-C₇-alkoxy, amino, nitro or cyano;        -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   C₁-C₇-alkyl-        -   halo-C₁-C₇-alkyl-        -   hydroxy-        -   C₁-C₇-alkoxy-        -   hydroxy-C₁-C₇-alkyl-;            or

    -   (C) phenyl,        -   substituted in ortho-position by            R³O—        -   and substituted in para- or meta-position by a substituent            selected from methyl or chloro;            or

    -   (D) (C-bound)-heterocycle selected from

-   -   -   wherein Z is a 4-6 membered heterocyclic ring, annulated to            phenyl in para and meta position, containing 1-3 heteroatoms            selected from N, O or S,

    -   which is optionally substituted by 1-2 additional substituents        selected from

    -   halogen-

    -   cyano-

    -   C₁-C₇-alkyl-

    -   halo-C₁-C₇-alkyl-

    -   hydroxy-

    -   C₁-C₇-alkoxy-

    -   hydroxy-C₁-C₇-alkyl-;        -   wherein R³ is independently selected from        -   H—        -   C₁-C₇-alkyl-        -   C₃-C₁₂-cycloalkyl-        -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-        -   (R⁵)₂N—C₁-C₇-alkyl-        -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-        -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-carbonyl-        -   R⁵O—C₃-C₁₂-cycloalkyl-        -   R⁵O—C₁-C₇-alkyl-        -   R⁵O—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-        -   R⁵O—C₃-C₁₂-cycloalkyl-carbonyl-        -   (R⁵)₂N-carbonyl-C₁-C₇-alkyl-        -   R⁵O-carbonyl-C₁-C₇-alkyl-        -   aryl-C₁-C₇-alkyl-        -   heterocyclyl-C₁-C₇-alkyl-        -   C₁-C₇-alkyl-carbonyl-        -   heterocyclyl-carbonyl-        -   aryl-carbonyl-        -   C₃-C₁₂-cycloalkyl-carbonyl-        -   C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-        -   heterocyclyl-        -   aryl-            -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are                unsubstituted or substituted by 1-4 substituents                selected from            -   halogen-            -   C₁-C₇-alkyl-            -   halo-C₁-C₇-alkyl-            -   C₁-C₇-alkyl-carbonyl-            -   C₃-C₁₂-cycloalkyl-carbonyl-            -   C₁-C₇-alkyl-sulfonyl-            -   amino-sulfonyl-            -   N—C₁-C₇-alkyl-amino-sulfonyl-            -   N,N-di-C₁-C₇-alkyl-amino-sulfonyl-            -   amino-carbonyl-            -   N—C₁-C₇-alkyl-amino-carbonyl-            -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-            -   oxo=        -   or        -   two R³, together with the N to which they are attached my            form a 3-9 membered heterocyclic ring, optionally containing            1-4 additional heteroatoms selected from N, O or S, said            heterocyclic ring is unsubstituted or substituted by 1-3            substituents selected from:        -   halogen-        -   halo-C₁-C₇-alkyl-        -   oxo=        -   hydroxy-        -   C₁-C₇-alkoxy-        -   amino-        -   N—C₁-C₇-alkyl-amino-        -   N,N-di-C₁-C₇-alkyl-amino-        -   hydroxy-carbonyl-        -   C₁-C₇-alkoxy-carbonyl-        -   amino-carbonyl-        -   N—C₁-C₇-alkyl-amino-carbonyl-        -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-        -   C₁-C₇-alkyl-carbonyl-        -   C₁-C₇-alkyl-carbonyl-amino-        -   C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-;        -   and        -   R⁵ is independently selected from:        -   H—        -   C₁-C₇-alkyl-        -   C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl-        -   amino-carbonyl-C₁-C₇-alkyl-        -   N—C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-        -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-        -   C₁-C₇-alkyl-sulfonyl-        -   amino-sulfonyl-        -   N—C₁-C₇-alkyl-amino-sulfonyl-        -   N,N-di-C₁-C₇-alkyl-amino-sulfonyl-        -   amino-carbonyl-        -   N—C₁-C₇-alkyl-amino-carbonyl-        -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-        -   C₃-C₁₂-cycloalkyl-carbonyl-        -   C₁-C₇-alkoxy-carbonyl-amino-C₁-C₇-alkyl-        -   C₁-C₇-alkoxy-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-        -   C₁-C₇-alkoxy-carbonyl-        -   or        -   two R⁵, together with the N to which they are attached my            form a 3-9 membered heterocyclic ring, optionally containing            1-4 additional heteroatoms selected from N, O or S, said            heterocyclic ring is unsubstituted or substituted by 1-3            substituent selected from        -   C₁-C₇-alkyl-        -   oxo=;

    -   with the proviso that if Z is CH₂, n is O and R² is selected        from

    -   para-C₁-C₃-alkyl-phenyl-

    -   para-(halo-C₁-C₃-alkyl)-phenyl-

    -   para-C₁-C₃-alkoxy-phenyl-

    -   para-halo-phenyl-

    -   para-nitro-phenyl-

    -   para-(C₁-C₃-alkoxy-carbonyl)-phenyl-

    -   para-(hydroxy-carbonyl)-phenyl-

    -   wherein the phenyl is optionally substituted by 1-2 additional        substituents, then R⁶ and R⁷ are not both ethoxy or methoxy.

In another embodiment,

Z is CH₂.

In another embodiment

Z is N—R⁴.

In another embodiment

Z is N—R⁴; wherein

R⁴ is selected from the group consisting of

H—,

C₁-C₄-alkyl-.

In another embodiment,

R⁶ is selected from

R′O—

and

R⁷ is selected from

R′O—.

In another embodiment,

R⁶ is selected from

H—

and

R⁷ is selected from

(R′)₂N—.

In another embodiment,

R′ is independently selected from the group consisting of

H—

C₁-C₇-alkenyl-

halo-C₁-C₇-alkyl-

C₃-C₁₂-cycloalkyl-

hydroxy-C₁-C₇-alkyl-

C₁-C₇-alkoxy-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-

N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-

heterocyclyl-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-

carbonyl-C₁-C₇-alkyl-

hydroxy-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl-

amino-carbonyl-C₁-C₇-alkyl-

N—C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-

N,N-di-C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-

heterocyclyl-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-

-   -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are        unsubstituted or substituted by 1-4 substituents selected from        C₁-C₇-alkyl, halo-C₁-C₇-alkyl, halogen, hydroxy, C₁-C₇-alkoxy,        amino, nitro or cyano.

In another embodiment,

R′ is independently selected from the group consisting of

H—

C₁-C₄-alkyl-

C₁-C₄-alkenyl-

halo-C₁-C₄-alkyl-

C₃-C₁₂-cycloalkyl-

C₃-C₁₂-cycloalkyl-C₁-C₂-alkyl-

-   -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are        unsubstituted or substituted by 1-2 substituents selected from        C₁-C₄-alkyl, halo-C₁-C₄-alkyl, halogen, hydroxy, C₁-C₄-alkoxy,        amino, nitro or cyano.

In another embodiment,

R¹ is independently selected from the group consisting of

halogen-

cyano-

nitro-

C₁-C₇-alkenyl-

halo-C₁-C₇-alkyl-

amino-

N—C₁-C₇-alkyl-amino-

hydroxy-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-

N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-.

In another embodiment,

R¹ is independently selected from the group consisting of

halogen-

cyano-

nitro-

C₁-C₄-alkyl-

C₁-C₄-alkenyl-

amino-

N—C₁-C₄-alkyl-amino-

hydroxy-C₁-C₂-alkyl-

amino-C₁-C₂-alkyl-

N—C₁-C₄-alkyl-amino-C₁-C₂-alkyl-

N,N-di-C₁-C₄-alkyl-amino-C₁-C₂-alkyl-

C₁-C₄-alkyl-carbonyl-amino-C₁-C₂-alkyl-.

In another embodiment,

n is 0 to 1.

In another embodiment,

n is 0.

In another embodiment,

R² is selected from

-   -   phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   and optionally substituted by 1-2 additional substituents        selected from    -   halogen-    -   cyano-    -   halo-C₁-C₇-alkyl-    -   hydroxy-    -   C₁-C₇-alkoxy-    -   hydroxy-C₁-C₇-alkyl.

In another embodiment,

-   -   R² is selected from    -   phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   and optionally substituted by 1-2 additional substituents        selected from    -   halogen-    -   cyano-    -   C₁-C₄-alkyl-    -   halo-C₁-C₄-alkyl-    -   hydroxy-    -   C₁-C₄-alkoxy-    -   hydroxy-C₁-C₄-alkyl,        wherein    -   R³ is independently selected from    -   H—    -   C₁-C₇-alkyl-    -   C₃-C₁₂-cycloalkyl-    -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-    -   (R⁵)₂N—C₁-C₇-alkyl-    -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-carbonyl-    -   R⁵O—C₁-C₇-alkyl-    -   (R⁵)₂N-carbonyl-C₁-C₇-alkyl-    -   R⁵O-carbonyl-C₁-C₇-alkyl-    -   aryl-C₁-C₇-alkyl-    -   heterocyclyl-C₁-C₇-alkyl-    -   C₁-C₇-alkyl-carbonyl-    -   heterocyclyl-carbonyl-    -   C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   heterocyclyl-        -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are            unsubstituted or substituted by 1-4 substituents selected            from        -   halo-        -   C₁-C₇-alkyl-        -   halo-C₁-C₇-alkyl-        -   C₁-C₇-alkyl-carbonyl-        -   C₃-C₁₂-cycloalkyl-carbonyl-        -   C₁-C₇-alkyl-sulfonyl-        -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-        -   oxo=    -   or    -   two R³, together with the N to which they are attached my form a        3-9 membered heterocyclic ring, optionally containing 1-4        additional heteroatoms selected from N, O or S, said        heterocyclic ring is unsubstituted or substituted by 1-3        substituents selected from:    -   C₁-C₇-alkyl-    -   oxo=    -   hydroxy-    -   amino-    -   N,N-di-C₁-C₇-alkyl-amino-    -   hydroxy-carbonyl-    -   C₁-C₇-alkoxy-carbonyl-    -   amino-carbonyl-    -   N—C₁-C₇-alkyl-amino-carbonyl-    -   C₁-C₇-alkyl-carbonyl-    -   C₁-C₇-alkyl-carbonyl-amino-;    -   and    -   R⁵ is independently selected from:    -   H—    -   C₁-C₇-alkyl-    -   C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl-    -   amino-carbonyl-C₁-C₇-alkyl-    -   C₁-C₇-alkyl-sulfonyl-    -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-    -   C₁-C₇-alkoxy-carbonyl-amino-C₁-C₇-alkyl-    -   C₁-C₇-alkoxy-carbonyl-    -   or    -   two R⁵, together with the N to which they are attached my form a        3-9 membered heterocyclic ring, optionally containing 1-4        additional heteroatoms selected from N, O or S, said        heterocyclic ring is unsubstituted or substituted by 1-3        substituent selected from    -   C₁-C₇-alkyl-    -   oxo=.

In another embodiment,

R² is selected from

-   -   phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   halo-C₁-C₇-alkyl-        -   hydroxy-        -   C₁-C₇-alkoxy-        -   hydroxy-C₁-C₇-alkyl,            wherein

    -   R³ is independently selected from:

    -   H—

    -   C₁-C₄-alkyl-

    -   C₃-C₁₂-cycloalkyl-

    -   (R⁵)₂N—C₃-C₇-cycloalkyl-

    -   (R⁵)₂N—C₁-C₇-alkyl-

    -   (R⁵)₂N—C₃-C₇-cycloalkyl-C₁-C₂-alkyl-

    -   (R⁵)₂N—C₃-C₇-cycloalkyl-carbonyl-

    -   aryl-C₁-C₂-alkyl-

    -   heterocyclyl-C₁-C₂-alkyl-

    -   C₁-C₄-alkyl-carbonyl-

    -   heterocyclyl-carbonyl-

    -   C₃-C₇-cycloalkyl-C₁-C₂-alkyl-

    -   heterocyclyl-        -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are            unsubstituted or substituted by 1-2 substituents selected            from        -   halo-        -   C₁-C₄-alkyl-        -   halo-C₁-C₄-alkyl-        -   C₁-C₄-alkyl-carbonyl-        -   C₃-C₇-cycloalkyl-carbonyl-        -   C₁-C₄-alkyl-sulfonyl-        -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-        -   oxo=

    -   or

    -   two R³, together with the N to which they are attached my form a        4-7 membered heterocyclic ring, optionally containing 1-2        additional heteroatoms selected from N, O or S, said        heterocyclic ring is unsubstituted or substituted by 1-2        substituents selected from:

    -   C₁-C₄-alkyl-

    -   oxo=

    -   hydroxy-

    -   amino-

    -   N,N-di-C₁-C₄-alkyl-amino-

    -   hydroxy-carbonyl-

    -   C₁-C₄-alkoxy-carbonyl-

    -   amino-carbonyl-

    -   N—C₁-C₄-alkyl-amino-carbonyl-

    -   C₁-C₄-alkyl-carbonyl-

    -   C₁-C₄-alkyl-carbonyl-amino-;

    -   and

    -   R⁵ is independently selected from:

    -   H—

    -   C₁-C₄-alkyl-

    -   C₁-C₄-alkoxy-carbonyl-C₁-C₂-alkyl-

    -   amino-carbonyl-C₁-C₂-alkyl-

    -   C₁-C₄-alkyl-sulfonyl-

    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-

    -   C₁-C₄-alkoxy-carbonyl-amino-C₁-C₂-alkyl-

    -   C₁-C₄-alkoxy-carbonyl-

    -   or

    -   two R⁵, together with the N to which they are attached my form a        4-7 membered heterocyclic ring, optionally containing 1-4        additional heteroatoms selected from N, O or S, said        heterocyclic ring is unsubstituted or substituted by 1-2        substituent selected from:

    -   C₁-C₄-alkyl-

    -   oxo=.

In another embodiment,

R² is selected from

-   -   phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond)        -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   halo-C₁-C₇-alkyl-        -   hydroxy-        -   C₁-C₇-alkoxy-        -   hydroxy-C₁-C₇-alkyl.

In another embodiment,

R² is selected from

-   -   phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein            -   (R³)₂N—Y— is selected from

-   -   -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   C₁-C₄-alkyl-        -   halo-C₁-C₄-alkyl-        -   hydroxy-        -   C₁-C₄-alkoxy-        -   hydroxy-C₁-C₄-alkyl.

In another embodiment, Z is CH₂ or NR⁴ wherein R⁴ is H or C₁-C₃-alkyl.Preferably, Z is CH₂ or NH, more preferably CH₂.

In another embodiment, X is chloro or fluoro, preferably chloro.

In another embodiment, each R′ is independently selected from

H—

C₁-C₆-alkyl-

heterocyclyl-C₁-C₄-alkyl-

amino-C₁-C₄-alkyl-

N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

heterocyclyl-carbonyl-C₁-C₄-alkyl-

hydroxy-C₁-C₄-alkyl-

amino-carbonyl-C₁-C₄-alkyl-

N—C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-

d₃ methoxy,

C₃-C₇-cycloalkyl-C₁-C₄-alkyl-

C₃-C₇-cycloalkyl-

aryl-C₁-C₄-alkyl-

C₁-C₄-alkoxy-C₁-C₄-alkyl-

C₁-C₆-alkenyl-

halo-C₁-C₄-alkyl-

halo-C₁-C₄-alkenyl-

C₁-C₄-alkyl-carbonyl-

C₁-C₄-alkyl-carbonyl-amino-C₁-C₄-alkyl-

aryl-C₁-C₄-alkyl-

heterocyclyl- and

aryl-

wherein said C₃-C₇-cycloalkyl (including the C₃-C₇-cycloalkylsubstituent within C₃-C₇-cycloalkyl-C₁-C₄-alkyl-), is optionallysubstituted by hydroxy or methyl, and wherein aryl (including withinaryl-C₁-C₄-alkyl-), and heterocyclyl (including withinheterocyclyl-C₁-C₄-alkyl- and heterocyclyl-carbonyl-C₁-C₄-alkyl-), isoptionally substituted by 1 or 2 C₁-C₄-alkyl substituents.

In another embodiment, at least one R′ is independently selected from

H—, and

C₁-C₆-alkyl-.

In another embodiment, R⁶ is selected from the group consisting of

H—

R′O— and

(R′)₂N—,

wherein R′ is independently selected from

H—

heterocyclyl-C₁-C₄-alkyl-

amino-C₁-C₄-alkyl-

heterocyclyl-carbonyl-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

hydroxy-C₁-C₄-alkyl-

N—C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-

and

d₃ methoxy,

wherein heterocyclyl within heterocyclyl-C₁-C₄-alkyl- andheterocyclyl-carbonyl-C₁-C₄-alkyl-, is optionally substituted by 1 or 2C₁-C₄-alkyl substituents.

In another embodiment, R⁷ is independently selected from

R′O—, and

(R′)₂N—,

wherein R′ is independently selected from

C₁-C₆-alkyl-

C₃-C₇-cycloalkyl-C₁-C₄-alkyl-

heterocyclyl-C₁-C₄-alkyl-

C₃-C₇-cycloalkyl-

heterocyclyl-C₁-C₄-alkyl-

hydroxy-C₁-C₄-alkyl-

amino-C₁-C₄-alkyl-

aryl-C₁-C₄-alkyl-

C₁-C₄-alkoxy-C₁-C₄-alkyl-

C₁-C₆-alkenyl-

halo-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-

C₁-C₄-alkyl-carbonyl-amino-C₁-C₄-alkyl-

aryl-C₁-C₄-alkyl-

wherein said C₃-C₇-cycloalkyl, or the C₃-C₇-cycloalkyl substituentwithin C₃-C₇-cycloalkyl-C₁-C₄-alkyl-, is optionally substituted byhydroxy.

Preferably, R⁶ is R′O—.

Preferably, R⁷ is R′O—.

In another embodiment, R′ is C₁-C₆-alkyl-.

In another embodiment, R¹ is independently selected from halogen,nitro-, C₁-C₄-alkyl, C₁-C₄-alkoxy-, amino, N—C₁-C₄-alkyl-amino-,N,N-di-C₁-C₄-alkyl-amino-, amino-carbonyl-amino-,N—C₁-C₄-alkyl-amino-carbonyl-amino-,N,N-di-C₁-C₄-alkyl-amino-carbonyl-amino-, amino-carbonyl-,N—C₁-C₄-alkyl-amino-carbonyl-, N,N-di-C₁-C₄-alkyl-amino-carbonyl-, C₁-C₄alkyl-carbonyl-amino-, hydroxy-C₁-C₄-alkyl-, amino-C₁-C₄-alkyl-,C₁-C₄-alkyl-carbonyl-amino-C₁-C₄-alkyl- andN—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-.

In another embodiment, R² is selected from:

-   -   (A) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   C₁-C₄-alkyl-        -   halo-C₁-C₄-alkyl-        -   hydroxy-        -   C₁-C₄-alkoxy-        -   hydroxy-C₁-C₄-alkyl-;

    -   (B) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by a substituent selected from        -   cyano-        -   halogen-        -   nitro-        -   C₁-C₄-alkyl-        -   halo-C₁-C₄-alkyl-        -   hydroxy-C₁-C₄-alkyl-        -   hydroxy-carbonyl-        -   C₁-C₄-alkoxy-carbonyl-        -   C₁-C₄-alkyl-carbonyl-        -   C₁-C₄-alkoxy-        -   (C-bound)-heterocyclyl-            -   wherein (C-bound)-heterocyclyl is unsubstituted or                substituted by 1-4 substituents selected from                C₁-C₄-alkyl, halo-C₁-C₄-alkyl, halogen, hydroxy,                C₁-C₄-alkoxy, amino, nitro or cyano;        -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   C₁-C₄-alkyl-        -   hydroxy-        -   C₁-C₄-alkoxy-        -   (C-bound or N-bound)heterocyclyl-C₁-C₄-alkyl-        -   hydroxy-C₁-C₄-alkyl-;            or

    -   (C) phenyl,        -   substituted in ortho-position by            R³O—            -   and substituted in para- or meta-position by a                substituent selected from methyl, chloro,                C₁-C₄-alkyl-carbonyl- or C₁-C₄-alkoxy-carbonyl-.

In another embodiment, R² is selected from:

-   -   (A) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   C₁-C₄-alkyl-        -   hydroxy-        -   C₁-C₄-alkoxy-        -   hydroxy-C₁-C₄-alkyl-.

In another embodiment, R² is selected from:

-   -   (A) phenyl, 2-pyridyl or 3-pyridyl,        -   substituted in para-position by (R³)₂N—Y—, wherein Y is            absent (a bond) and optionally substituted by 1-2 additional            substituents selected from        -   halogen-        -   cyano-        -   C₁-C₄-alkyl-        -   hydroxy-        -   C₁-C₄-alkoxy-        -   hydroxy-C₁-C₄-alkyl-.

In another embodiment, R² is selected from:

-   -   (A) phenyl, 2-pyridyl or 3-pyridyl,        -   substituted in para-position by (R³)₂N—Y—, wherein Y is            absent (a bond), and wherein the phenyl, 2-pyridyl or            3-pyridyl are not further substituted.

In another embodiment, each R³ is independently selected from:

C₁-C₄-alkyl-

C₃-C₇-cycloalkyl-C₁-C₄-alkyl-

heterocyclyl-C₁-C₄-alkyl-

aryl-C₁-C₄-alkyl-

(R⁵)₂N—C₃-C₇-cycloalkyl-

(R⁵)₂N—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-

(R⁵)₂N—CO—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-

aryl-

heterocyclyl-

C₃-C₇-cycloalkyl-

wherein aryl, heterocyclyl and C₃-C₇-cycloalkyl are unsubstituted orsubstituted by 1-4 substituents selected from

-   -   halogen-    -   C₁-C₄-alkyl-    -   C₁-C₄-alkyl-carbonyl-    -   C₃-C₇-cycloalkyl-carbonyl-    -   C₁-C₄-alkyl-sulfonyl-    -   amino-sulfonyl-    -   N—C₁-C₄-alkyl-amino-sulfonyl-    -   N,N-di-C₁-C₄-alkyl-amino-sulfonyl-    -   amino-carbonyl-    -   N—C₁-C₄-alkyl-amino-carbonyl-    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl- and    -   oxo=

In another embodiment, R² is selected from (A) phenyl, 2-pyridyl or3-pyridyl, substituted in para-position by (R³)₂N—Y—, wherein Y isabsent (a bond), wherein one R³ is C₁-C₄-alkyl-, preferably methyl, andthe other R³ is selected from:

C₃-C₇-cycloalkyl-C₁-C₄-alkyl-

heterocyclyl-C₁-C₄-alkyl-

(R⁵)₂N—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-

(R⁵)₂N—CO—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-

wherein aryl, heterocyclyl and C₃-C₇-cycloalkyl are unsubstituted orsubstituted by 1-4 substituents independently selected from:

halogen-, C₁-C₄-alkyl-, C₁-C₄-alkyl-carbonyl-,C₃-C₇-cycloalkyl-carbonyl-, C₁-C₄-alkyl-sulfonyl-, amino-sulfonyl-,N—C₁-C₄-alkyl-amino-sulfonyl-, N,N-di-C₁-C₄-alkyl-amino-sulfonyl-,amino-carbonyl-, N—C₁-C₄-alkyl-amino-carbonyl-,N,N-di-C₁-C₄-alkyl-amino-carbonyl- and oxo=.

In another embodiment, R² is selected from (A) phenyl, 2-pyridyl or3-pyridyl, substituted in para-position by (R³)₂N—Y—, wherein Y isabsent (a bond), wherein one R³ is C₁-C₄-alkyl-, preferably methyl, andthe other R³ is selected from the group including(R⁵)₂N—C₃-C₇-cycloalkyl-C₁-C₄-alkyl- and(R⁵)₂N—CO—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-, and the two R⁵, together withthe N to which they are attached form a 3, 4, 5, 6 or 7 memberedheterocyclic ring, optionally containing 1, 2, 3 or 4 additional Nheteroatoms and/or optionally containing a O atom and/or a S atom, saidheterocyclic ring being unsubstituted or substituted by from 1, 2 or 3substituents independently selected from

-   -   C₁-C₄-alkyl-    -   oxo=,    -   C₁-C₄-alkyl-carbonyl,    -   C₁-C₄-alkyl-sulphonyl, and    -   hydroxy-C₁-C₄-alkyl.

In a preferred embodiment, R² is selected from (A) phenyl, 2-pyridyl or3-pyridyl, substituted in para-position by (R³)₂N—Y—, wherein Y isabsent (a bond), and wherein one R³ is C₁-C₄-alkyl-, preferably methyl,and the other R³ is (R⁵)₂N-cyclohexyl-C₁-C₂-alkyl-, and wherein the twoR⁵, together with the N to which they are attached form a 6 memberedheterocyclic ring, optionally containing 1 additional N heteroatomand/or optionally containing a O atom and/or a S atom, said heterocyclicring being unsubstituted or substituted by 1 or 2 substituentsindependently selected from

-   -   C₁-C₄-alkyl-, preferably methyl    -   oxo=,    -   C₁-C₄-alkyl-carbonyl,    -   C₁-C₄-alkyl-sulphonyl, and    -   hydroxy-C₁-C₄-alkyl.

In a more preferred embodiment, R² is selected from phenyl or 3-pyridyl,substituted in para-position by (R³)₂N—Y—, wherein Y is absent (a bond),and wherein one R³ is C₁-C₄-alkyl-, preferably methyl, and the other R³is (R⁵)₂N-cyclohexyl-methyl-, and wherein the two R⁵, together with theN to which they are attached, form a 6 membered heterocyclic ringcontaining 1 additional N heteroatom, said heterocyclic ring beingsubstituted at a carbon atom by an oxo substituent and optionallyN-substituted by methyl. Preferably said heterocyclic ring ispiperazinyl. Preferably, the cyclohexyl ring is substituted at the 1 and4 positions. Preferably, the stereochemistry of such substitution istrans.

In another embodiment, each R⁵ is independently selected from:

-   -   H—    -   C₁-C₄-alkyl-    -   hydroxy-C₁-C₄-alkyl-    -   C₁-C₄-alkyl-carbonyl-    -   C₁-C₄-alkoxy-carbonyl-C₁-C₄-alkyl-    -   amino-carbonyl-C₁-C₄-alkyl-    -   N—C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-    -   C₁-C₄-alkyl-sulfonyl-    -   amino-sulfonyl-    -   N—C₁-C₄-alkyl-amino-sulfonyl-    -   N,N-di-C₁-C₄-alkyl-amino-sulfonyl-    -   heterocyclyl-carbonyl-    -   amino-carbonyl-    -   N—C₁-C₄-alkyl-amino-carbonyl-    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-    -   C₃-C₇-cycloalkyl-carbonyl-    -   C₁-C₄-alkoxy-carbonyl-amino-C₁-C₄-alkyl-    -   C₁-C₄-alkoxy-carbonyl-N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-    -   C₁-C₄-alkoxy-carbonyl-    -   C₃-C₇-cycloalkyl-    -   hydroxy-C₃-C₇-cycloalkyl-    -   or    -   two R⁵, together with the N to which they are attached may form        a 3, 4, 5, 6 or 7 membered heterocyclic ring, optionally        containing 1, 2, 3 or 4 additional N heteroatoms and/or        optionally containing a O atom and/or a S atom, said        heterocyclic ring being unsubstituted or substituted by from 1,        2 or 3 substituents independently selected from    -   C₁-C₄-alkyl-    -   oxo=,    -   C₁-C₄-alkyl-carbonyl,    -   C₁-C₄-alkyl-sulphonyl,    -   hydroxy-C₁-C₄-alkyl;

In a further embodiment of the invention as described herein, when twoR³ substituents are present and they do not join to form a ring, atleast one R³ substituent is selected from hydrogen, C₁-C₄-alkyl,C₁-C₄-alkoxycarbonyl and C₁-C₄-alkylcarbonyl. Preferably at least one R³substituent is selected from H, methyl and ethyl, particularly methyl.In another embodiment, at least one R³ is C₁-C₇-alkyl-, preferablyC₁-C₄-alkyl-, preferably methyl.

In another embodiment, when R³ includes a cyclohexylalkyl group which isfurther monosubstituted at a cyclohexyl ring atom, the cyclohexylsubstitution is preferably at the 1 and 4 positions. Such substitutionpattern is illustrated as an example below, and is not limited to thefollowing specific example:

In another embodiment, the stereochemistry of such substitution istrans. An example of such stereochemistry is provided below, and is notlimited to the following specific example:

In another embodiment, the stereochemistry of the compound of formula Iis shown below:

In another embodiment, R⁶ is selected from H, hydroxy, methoxy, ethoxy,propoxy (isopropoxy or n-propoxy), butoxy (preferably isobutoxy),morpholin-4-ylethoxy, aminoethoxy,4-methylpiperazin-1-ylcarbonylmethoxy, dimethylaminoethoxy,dimethylaminopropoxy, hydroxyethoxy, hydroxypropoxy,dimethylaminocarbonylmethoxy, methylaminocarbonylmethoxy and d₃ methoxy.

Preferably R⁶ is methoxy.

In another embodiment, R⁷ is selected from methoxy, ethoxy, butoxy(including isobutoxy, sec-butoxy, (R)-sec-butoxy, (S)-sec-butoxy),propoxy (including isopropoxy, n-propoxy), cyclopropylmethoxy,cyclopentyloxy, morpholinyl-4-ylpropoxy, 3-hydroxypropoxy,3-dimethylaminopropoxy, 1-ethylpropoxy, 3-aminopropoxy, cyclobutoxy,1-methylbutoxy, 1,2-dimethylpropoxy, 3-amino-1-methyl-propoxy,cyclohexyloxy, benzyloxy, cyclohexylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, 2-methoxy-1-methyl-ethoxy (including in particular(R) 2-methoxy-1-methyl-ethoxy), 1,3-dimethyl-but-3-enyloxy,1-methyl-but-3-enyloxy, pyridin-4-ylmethoxy, trifluoromethoxy,methoxyethoxy, (R) tetrahydrofuran-2-ylmethoxy, (S)tetrahydrofuran-2-ylmethoxy, (R)-2-methoxy-propoxy,2-methoxy-1-methyl-ethoxy, 1-hydroxy-cyclopropylmethoxy,3-methoxy-propoxy, oxetan-2-ylmethoxy, 2,2-difluoro-ethoxy,isopropylamino, ethylcarbonylamino, isopropyl-propyl-amino,(dimethylaminoethyl)-isopropyl-amino,(methylcarbonylaminoethyl)isopropylamino, isobutylamino,cyclopentylmethylamino, 1-ethyl-propyl-amino, cyclohexylamino,butylamino (including sec-butylamino), cyclobutylamino,cyclopentylamino, propylamino, ethylamino, benzylamino,cyclopropylmethylamino, cyclohexylmethylamino, methylcarbonylamino,isopropylcarbonylamino, (methylcarbonyl)isopropylamino,(ethylcarbonyl)isopropylamino, (isopropyl)methyl-amino and(isopropyl)ethyl-amino. Preferably R⁷ is isopropoxy.

In a preferred embodiment, n is 0.

In another embodiment, R¹ is selected from hydrogen, fluoro, chloro,methyl, methoxy, bromo, nitro, amino, amino-carbonyl-amino-,methylaminocarbonylamino-, methylaminocarbonyl-, methylcarbonylamino-,ethylaminocarbonylamino-, ethylcarbonylamino-, (ethyl)methylamino-,dimethylamino-, aminocarbonyl-, hydroxymethyl-, aminomethyl-,methylcarbonylaminomethyl-, methylaminomethyl.

In a preferred embodiment, R² is selected from:

-   -   (A) i phenyl substituted by:

4-dimethylamino-, 4-methylamino-, 4-morpholin-4-yl-, 4-pyrrolidin-1-yl-,4-dimethylamino-2-methoxy, 2-methoxy-4-methyl-,2-methoxy-4-morpholin-4-yl-, 4-dimethylamino-2-methoxy-,4-dimethylamino-2-methyl-, 4-(N-methyl-N-pyridin-4-ylmethyl-amino)-,4-(2-oxo-pyrrolidin-1-yl)-, 4-pyrazol-1-yl-, 4-methylcarbonylamino-,4-(2-oxo-azetidin-1-yl)-, 4-(N-methyl-N-ethyl-amino)carbonyl-,4-(piperidine-1-carbonyl), 4-methylaminocarbonyl,4-diethylaminocarbonyl-, 4-dimethylaminocarbonyl,4-(pyrrolidine-1-carbonyl)-, 4-aminocarbonyl-,4-(N-methyl-N-pyridin-4-yl-aminocarbonyl)-,4-(N-pyridin-4-yl-aminocarbonyl)-, 4-(N-pyridin-3-yl-aminocarbonyl)-,4-hydroxymethyl, 4-N-methylcarbonyl-N-methyl-amino-,4-(N-methylcarbonyl-N-cyclopentylmethyl-amino)-,4-(N-methyl-N-piperidin-3-yl-methyl-amino)-,4-[methyl-(1-methyl-piperidin-3-ylmethyl)-amino]-,4-(N-methyl-N-piperidin-4-ylmethyl-amino)-,4-[(1-Acetyl-piperidin-4-ylmethyl)-methyl-amino]-,4-[(1-methanesulfonyl-piperidin-4-ylmethyl)-methyl-amino]-,4-[(4-Amino-cyclohexylmethyl)-methyl-amino]-,4-[(4-ethylamino-cyclohexylmethyl)-methyl-amino]-,4-{[4-(ethyl-methyl-amino)-cyclohexylmethyl]-methyl-amino}-,4-diethylamino, 4-(N-cyclopentylmethyl-N-methyl-amino)-,4-(N-isopropyl-N-methyl-amino)-, 4-(N-cyclopentyl-N-methyl-amino)-,4-(N-cyclohexyl-N-methyl-amino)-, 4-(N-sec-butyl-N-methyl-amino)-,4-(N-cyclopropylmethyl-N-methyl-amino)-,4-(N-cyclohexylmethyl-N-methyl-amino)-, 4-(N-isobutyl-N-methyl-amino)-,4-(N-Benzyl-N-methyl-amino)-, 4-(N-ethyl-N-methyl-amino)-,4-ethylamino-, 4-dipropylamino-, 4-(N-cyclobutyl-N-methyl-amino)-,4-[(2-fluoro-benzyl)-methyl-amino]-,4-[(2,3-difluoro-benzyl)-methyl-amino]-,4-[methyl-(3-trifluoromethyl-benzyl)-amino]-,4-[methyl-(4-trifluoromethyl-benzyl)-amino]-,4-[(3-fluoro-benzyl)-methyl-amino]-,4-(N-methyl-N-pyridin-3-ylmethyl-amino)-,4-[(4-fluoro-benzyl)-methyl-amino]-,4-[(3,4-difluoro-benzyl)-methyl-amino]-,4-[(pyridin-4-ylmethyl)-amino]-,4-(N-cyclopropylmethyl-N-pyridin-4-ylmethyl-amino)-,4-(N-ethyl-N-pyridin-4-ylmethyl-amino)-,4-[(2-morpholin-4-yl-ethyl)-pyridin-4-ylmethyl-amino]-,4-(N-methyl-N-pyrimidin-4-ylmethyl-amino)-,4-[(3-fluoro-pyridin-4-ylmethyl)-methyl-amino]-,4-(N-methyl-N-thiophen-3-ylmethyl-amino)-,4-[methyl-(3-methyl-3H-imidazol-4-ylmethyl)-amino]-,4-(N-furan-3-ylmethyl-N-methyl-amino)-,4-[methyl-(2-morpholin-4-yl-ethyl)-amino]-,4-[methyl-(1-methyl-piperidin-4-ylmethyl)-amino]-,4-[methyl-(4-propylamino-cyclohexylmethyl)-amino]-,4-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-,4-[(4-amino-cyclohexylmethyl)-methyl-amino]-,4-[(4-dimethylamino-cyclohexylmethyl)-ethyl-amino]-,4-[methyl-(4-pyrrolidin-1-yl-cyclohexylmethyl)-amino]-,4-[methyl-(4-piperidin-1-yl-cyclohexylmethyl)-amino]-,[4-(methyl-piperidin-4-ylmethyl-amino)-,4-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-cyclohexylmethyl]-amino}-,4-(3-amino-1H-pyrazol-4-yl)-, 4-(3-Amino-5-methyl-1H-pyrazol-4-yl)-,4-(3,5-dimethyl-1H-pyrazol-4-yl)-, 4-(1-pyrrolidin-1-yl-ethyl)-,4-(1-morpholin-4-yl-ethyl)-, 4-(1-hydroxy-ethyl)-,4-[1-(piperidin-4-ylamino)-ethyl],4-[1-(N-piperidin-4-yl-N-methylcarbonyl-amino)ethyl],4-[1-(N-methyl-N-piperidin-4-yl-amino)-ethyl]-,4-{1-[(4-dimethylamino-cyclohexyl)-methyl-amino]ethyl}-,4-[1-(4-amino-cyclohexylamino)-ethyl]-,4-[1-(4-dimethylamino-piperidin-1-yl)-ethyl]-,4-(1-[4-(isopropyl-methyl-amino)-piperidin-1-yl]-ethyl}-,4-(1-dimethylamino-ethyl)-, 4-[1-(4-hydroxy-piperidin-1-yl)-ethyl],4-[1-(2-dimethylamino-ethylamino)-ethyl]-,4-[1-((R)-3-hydroxy-pyrrolidin-1-yl)-ethyl],4-[1-((S)-3-hydroxy-pyrrolidin-1-yl)-ethyl],4-[1-((S)-3-hydroxy-piperidin-1-yl)-ethyl],4-[1-((R)-3-hydroxy-piperidin-1-yl)-ethyl],4-(1-thiomorpholin-4-yl-ethyl)-,4-(1-N-isobutyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-propyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-isopropyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclopropyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclohexylmethyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclopentyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclohexyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclopropylmethyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclopentylmethyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-benzyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclobutyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-pyrrolidine-3-carbonyl-N-ethyl-amino-ethyl)-,4-(1-N-cis-4-amino-cyclohexanecarbonyl-N-ethyl-amino-ethyl)-,4-(1-N-trans-4-amino-cyclohexanecarbonyl-N-ethyl-amino-ethyl)-,4-(1-N-4-dimethylamino-cyclohexanecarbonyl-N-ethyl-amino-ethyl)-,4-(1-N-4-dimethylamino-cyclopentanecarbonyl-N-ethyl-amino-ethyl)-,4-(1-N-1-methyl-pyrrolidine-3-yl-carbonyl-N-ethyl-amino-ethyl)-,4-(1-N-4-dimethylamino-cyclohexanecarbonyl-N-ethyl-amino-ethyl)-,4-[1-(piperidin-3-ylamino)-ethyl],4-(1-N-(2-aminoethyl)-N-methylcarbonyl-amino-ethyl)-,4-(1-N-(2-dimethylaminoethyl)-N-methylcarbonyl-amino-ethyl)-,4-(1-N-(3-aminopropyl)-N-methylcarbonyl-amino-ethyl)-,4-(1-N-(3-dimethylaminopropyl)-N-methylcarbonyl-amino-ethyl)-,4-[1-(N-ethyl-N-piperidin-4-yl-amino)-ethyl]-,4-[1-(3-Amino-piperidin-1-yl)-ethyl],4-[1-((R)-3-Amino-pyrrolidin-1-yl)-ethyl],4-[1-((S)-3-Amino-pyrrolidin-1-yl)-ethyl]-,4-[1-(3-dimethylamino-pyrrolidin-1-yl)-ethyl],[1-(4-diethylamino-piperidin-1-yl)-ethyl],4-[1-(3-oxo-morpholin-4-yl)-ethyl],4-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-,4-(N-methyl-N-ethyl-amino-carbonyl)-,4-(N-cyclopropylmethyl-N-methyl-amino)-, 4-(2-oxo-azetidin-1-yl),4-(1-N-methylcarbonyl-N-ethyl-amino-ethyl),4-(morpholin-4-yl-cyclohexylmethyl)-amino]-,4-(morpholin-4-yl-cyclohexylmethyl)-methyl-amino]-,4-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-3-methyl-,4-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-3-fluoro-,4-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-2-methoxy-,4-[1-(4-Acetyl-piperazin-1-yl)-ethyl],4-[1-(4-dimethylamino-piperidin-1-yl)-ethyl]-,4-[(-4-dimethylamino-cyclohexylmethyl)-methyl-amino]-,4-[(-4-dimethylamino-cyclohexylmethyl)-ethyl-amino]-,4-[2-(4-dimethylamino-piperidin-1-yl)-1-methyl-ethyl],4-[2-(4-dimethylamino-piperidin-1-yl)-1-methyl-2-oxo-ethyl]-,4-imidazol-1-ylmethyl-, 4-(N-trifluoromethyl-carbonyl-N-methyl-amino)-,4-[1-(2-oxo-piperazin-1-yl)-ethyl]-,4-(2-hydroxy-ethyl)-2-oxo-piperazin-1-yl]-ethyl}-,4-[1-(methylcarbonylamino)-ethyl]-,4-[1-(methoxymethylcarbonylamino)-ethyl],4-[1-(dimethylamino-methyl-carbonylamino)-ethyl],4-(2-oxo-pyrrolidin-1-yl), 4-(2-oxo-imidazolidin-1-yl)- or4-(3-amino-5-ethyl-1H-pyrazol-4-yl)-, or

R² is selected from phenyl substituted by:

2-fluoro or 3-fluoro and substituted in the para position (relative tothe isoquinolinone or quinazolinone), by:

or R² is selected from phenyl substituted in the ortho position(relative to the isoquinolinone or quinazolinone), by methoxy andsubstituted in the para position (relative to the isoquinolinone orquinazolinone), by:

or R² is phenyl substituted in the para position (relative to theisoquinolinone or quinazolinone), by:

-   (A) ii or R² is 2-pyridyl (relative to the isoquinolinone or    quinazolinone), substituted by:    5-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-,    5-[(4-amino-cyclohexylmethyl)amino]-,

-   (A) iii or R² is 3-pyridyl (relative to the isoquinolinone or    quinazolinone), substituted by:    6-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]- or    6-[(3-hydroxy-cyclobutylmethyl)-methyl-amino]-,-   or R² is 3-pyridyl (relative to the isoquinolinone or    quinazolinone), substituted in the 6 position by:    6-{methyl-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylmethyl]-amino}-,    6-{methyl-[4-(2-oxo-imidazolidin-1-yl)cyclohexylmethyl]-amino}-,

or R² is 3-pyridyl (relative to the isoquinolinone or quinazolinone),substituted by: 2 fluoro-6-

-   (B) i or R² is phenyl substituted by:    -   4-methoxy, 4-cyano, 3,4-dimethyl, 2,4-dimethyl,        4-methoxy-2-methyl-, 2-chloro-4-methyl-, 2,4-dimethoxy-,        3,4-dichloro-, 4-methyl-, 3,4-dimethoxy, 2-methoxy-4-methyl-,        4-(1H-pyrazol-4-yl)-, 4-(3,5-dimethyl-1H-pyrazol-4-yl)-,

-   -   (B) ii or R² is 2-pyridyl (relative to the isoquinolinone or        quinazolinone), substituted by 4-methyl,    -   (B) iii or R² is 3-pyridyl (relative to the isoquinolinone or        quinazolinone), substituted by 4-methyl,    -   (C) or R² is phenyl substituted by:        -   4-methyl-2-(3-morpholin-4-yl-propoxy)-,            4-methyl-2-hydroxycarbonylmethoxy-, 2-methoxy-5-methyl-,            4-methyl-2-(2H-tetrazol-5-ylmethoxy)-,            4-methyl-2-(thiazol-5-ylmethoxy)-,            4-methoxycarbonyl-2-tetrazol-5-ylmethoxy,            4-methoxycarbonyl-2 methoxy,            4-methoxycarbonyl-2-thiazol-5-ylmethoxy)-,            4-methyl-2-(2-morpholin-4-yl-ethoxy),            2-(3-dimethylamino-propoxy)-4-methyl-,            4-methyl-2-[2-(4-methyl-piperazin-1-yl)-ethoxy]-,            4-methyl-2-[3-(4-methyl-piperazin-1-yl)-propoxy]-,            2-methoxycarbonylmethoxy-5-chloro-,            2-hydroxycarbonylmethoxy-5-chloro-,            5-chloro-2-(2-dimethylamino-ethoxy)-,            5-chloro-2-(3-morpholin-4-yl-propoxy)-,            5-chloro-2-(2-morpholin-4-yl-ethoxy)-,            5-chloro-2-(3-dimethylamino-propoxy)-,            5-chloro-2-(3-hydroxy-propoxy)- or            5-chloro-2-(2-hydroxy-ethoxy)-,    -   (D) or R² is (C-bound)-heterocycle selected from benzofuran-5-yl        and 1-methyl-1H-indazol-5-yl,    -   (E) or R² is pyrazin-2-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 5 position by:

-   -   (F) or R² is pyridazin-3-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 6 position by:

-   -   (G) or R² is pyrimidin-2-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 5 position by:

In another embodiment there is provided a compound of formula I or saltthereof as described herein, with the proviso that

-   -   if Z is CH₂, n is 0 or 1, so that when n is 1 then R¹ is        ortho-chloro, and R² is    -   selected from    -   para-C₁-C₃-alkyl-phenyl-    -   para-(halo-C₁-C₃-alkyl)-phenyl-    -   para-C₁-C₃-alkoxy-phenyl-    -   para-halo-phenyl-    -   para-nitro-phenyl-    -   para-(C₁-C₃-alkoxy-carbonyl)-phenyl-    -   para-(hydroxy-carbonyl)-phenyl-    -   wherein the phenyl is optionally substituted by 1-2 additional        substituents, said substituents being independently selected        from halo and methyl,    -   then R⁶ and R⁷ are not both ethoxy or methoxy.

As already indicated above, p53 refers to the human protein itself asdescribed by Matlashewski et al. in EMBO J. 3, 3257-62 (1984) or relatedfamily members (e.g. p73 as described in Kaghad et al. in Cell 90,809-19 (1997) and p63 as described in Yang et al in Mol Cell 2, 305-16(1998)) (named also p53 wild type herein) or to any variant thereof(e.g. a splice variant, mutant, fragment or isoform due to deletion,insertion and/or exchange of one or more, e.g. one to 200, of the aminoacids) that is still capable to retain preferably at least 1%, morepreferably at least 5%, yet more preferably at least 10%, 20%, 30%, 40%,50% or more than 50% of the p53 activity in growth suppression, e.g. inthe growth suppression assay described in Pietenpol et al., Proc. Nat.Acad. Sci. USA 91, 1998-2002 (1994) and, if compared with thecorresponding sequence of p53 wild type, shows at least 20%, morepreferably at least 25% identity with the full sequence, e.g. at least90% identity with a partial sequence thereof. Where not mentionedotherwise, p53 generally relates to TP53, p53, TP73, p73, TP63, TP73L,p63, or variants thereof, respectively, as just defined.

As already indicated above, MDM2 (especially when mentioned as MDM2 orvariants thereof) generally refers to all genes and/or proteins encodedthereof with the names MDM2, Mdm2, HDM2, Hdm2, or a variant thereof.MDM4 (especially when mentioned as MDM4 or variants thereof) refers toall genes and/or proteins encoded thereof with the names MDM4, Mdm4,HDM4, Hdm4, MDMX, MdmX, HDMX, HdmX, or a variant thereof.

MDM2 specifically relates to MDM2 as described in EMBO J. 10, 1565-9,Fakharzadeh et al., 1991, a variant thereof refers to a variant thereofwhich still binds to p53 in the assay system described below (e.g. asplice variant, isoform, fragment, mutant or oncogene due to deletion,insertion and/or exchange of one or more, e.g. one to 430, of the aminoacids), corresponding to the full length proteins as originallydescribed, preferably at least with 0.5%, more preferably at least with5%, 10%, 20%, 30%, 40% or especially 50% or more of the affinity of MDM2to p53, and have at least 20%, more preferably at least 25%, sequenceidentity to MDM2 or to HDM2 as originally described or as mentionedbelow specifically. Where not mentioned otherwise, MDM2 generallyrelates to MDM2, Mdm2, HDM2 or Hdm2, or variants thereof, respectively,as just defined.

MDM4 specifically relates to MDM4 as described in Genomics 43, 34-42,Shvarts et al., 1997, a variant thereof refers to a variant thereofwhich still binds to p53 in the assay system described below (e.g. asplice variant, isoform, fragment, mutant or oncogene due to deletion,insertion and/or exchange of one or more, e.g. one to 430, of the aminoacids), corresponding to the full length proteins as originallydescribed, preferably at least with 0.5%, more preferably at least with5%, 10%, 20%, 30%, 40% or especially 50% or more of the affinity of MDM4to p53, and have at least 20%, more preferably at least 25%, sequenceidentity to MDM4, to MDMX, to HDM4 or to HDM2 as originally described oras mentioned below specifically. Where not mentioned otherwise, MDM4generally relates to MDM4, Mdm4, HDM4, Hdm4, MDMX, MdmX, HDMX or HdmX,or variants thereof, respectively, as just defined.

The percentage of sequence identity, often also termed homology, betweena protein and a variant thereof is preferably determined by a computerprogram commonly employed for this purpose, such as the Gap program(Wisconsin Sequence Analysis Package, Version 8 for Unix, GeneticsComputer Group, University Research Park, Madison Wis., USA, which usesthe algorithm of Smith and Waterman (Adv. Appl. Math. 2: 482-489(1981)., especially using an affine gap search with a gap open penaltyof 12 and a gap extension penalty of 1.

“Variants thereof” where mentioned means one or more variant(s).

A proto-oncogene is a normal gene that can become an oncogene, eitherafter mutation or increased expression. Proto-oncogenes code forproteins that help to regulate cell growth and differentiation.Proto-oncogenes are often involved in signal transduction and executionof mitogenic signals, usually through their protein products. Uponactivation, a proto-oncogene (or its product) becomes a tumor inducingagent, an oncogene.

Compounds of the formula (I) may have different isomeric forms. As usedherein, the term “an optical isomer” or “a stereoisomer” refers to anyof the various stereo isomeric configurations which may exist for agiven compound of the present invention and includes geometric isomers.It is understood that a substituent may be attached at a chiral centerof a carbon atom. Therefore, the invention includes enantiomers,diastereomers or racemates of the compound. “Enantiomers” are a pair ofstereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term isused to designate a racemic mixture where appropriate.“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line. Certain ofthe compounds described herein contain one or more asymmetric centers oraxes and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, including racemic mixtures, opticallypure forms and intermediate mixtures. Optically active (R)- and(S)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques. If the compound contains adouble bond, the substituent may be E or Z configuration. If thecompound contains a disubstituted cycloalkyl, the cycloalkyl substituentmay have a cis- or trans-configuration. All tautomeric forms are alsointended to be included.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which typically are not biologically orotherwise undesirable. In many cases, the compounds of the presentinvention are capable of forming acid and/or base salts by virtue of thepresence of amino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulformate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns 1 to 12 of the periodic table. Incertain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods.

Generally, such salts can be prepared by reacting free acid forms ofthese compounds with a stoichiometric amount of the appropriate base(such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two.

Generally, use of non-aqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile is desirable, where practicable. Lists ofadditional suitable salts can be found, e.g., in “Remington'sPharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton,Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties,Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002).

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed.

In view of the close relationship between the novel compounds of theformula (I) in free form and those in the form of their salts, includingthose salts that can be used as intermediates, for example in thepurification or identification of the novel compounds, any reference tothe compounds or a compound of the formula (I) hereinbefore andhereinafter is to be understood as referring to the compound in freeform and/or also to one or more salts thereof, as appropriate andexpedient, as well as to one or more solvates, e.g. hydrates.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C_(,) ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H, ¹³C, and ¹⁴C, are present. Such isotopicallylabelled compounds are useful in metabolic studies (with ¹⁴C), reactionkinetic studies (with, for example ²H or ³H), detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Isotopically-labeled compounds of the formula (I) can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Preparations using an appropriate isotopically-labeled reagents inplace of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of the formula (I) thatcontain groups capable of acting as donors and/or acceptors for hydrogenbonds may be capable of forming co-crystals with suitable co-crystalformers. These co-crystals may be prepared from compounds of the formula(I) by known co-crystal forming procedures. Such procedures includegrinding, heating, co-subliming, co-melting, or contacting in solutioncompounds of the formula (I) with the co-crystal former undercrystallization conditions and isolating co-crystals thereby formed.Suitable co-crystal formers include those described in WO 2004/078163.Hence the invention further provides co-crystals comprising a compoundof the formula (I).

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, and the like and combinations thereof, as would be known to thoseskilled in the art (see, for example, Remington's PharmaceuticalSciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Exceptinsofar as any conventional carrier is incompatible with the activeingredient, its use in the therapeutic or pharmaceutical compositions iscontemplated.

By “combination”, there is meant either a fixed combination in onedosage unit form, or a kit of parts for the combined administrationwhere a compound of the formula (I) and a combination partner may beadministered independently at the same time or separately within timeintervals that especially allow that the combination partners show acooperative, e.g. synergistic effect.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by the dysregulation of the p53/MDM2 ratio, or(ii) associated with the dysregulation of the p53/MDM2 ratio, or (iii)characterized by the dysregulation of the MDM2/p53 ratio; or (2)reducing or inhibiting the activity of the p53/MDM2 interaction. Inanother non-limiting embodiment, the term “a therapeutically effectiveamount” refers to the amount of the compound of the present inventionthat, when administered to a cell, or a tissue, or a non-cellularbiological material, or a medium, is effective to at least partiallyreducing or inhibiting the p53/MDM2 interaction.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal.

A subject also refers to for example, primates (e.g., humans), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds andthe like. In certain embodiments, the subject is a primate. In yet otherembodiments, the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known to those skilled in the art into theindividual isomers; diastereoisomers can be separated, for example, bypartitioning between polyphasic solvent mixtures, recrystallisationand/or chromatographic separation, for example over silica gel or bye.g. medium pressure liquid chromatography over a reversed phase column,and racemates can be separated, for example, by the formation of saltswith optically pure salt-forming reagents and separation of the mixtureof diastereoisomers so obtainable, for example by means of fractionalcrystallisation, or by chromatography over optically active columnmaterials.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Compounds of the present invention are either obtained in the free form,as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention may also form internalsalts, e.g., zwitterionic molecules.

The present invention also provides pro-drugs of the compounds of thepresent invention that converts in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally, bioprecursorprodrugs are compounds, which are inactive or have low activity comparedto the corresponding active drug compound, that contain one or moreprotective groups and are converted to an active form by metabolism orsolvolysis. Both the active drug form and any released metabolicproducts should have acceptably low toxicity.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. Carrier prodrugs can, forexample, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g., stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof (a) hydroxyl groups with lipophilic carboxylic acids (e.g., acarboxylic acid having at least one lipophilic moiety), or (b)carboxylic acid groups with lipophilic alcohols (e.g., an alcohol havingat least one lipophilic moiety, for example aliphatic alcohols).

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acylderivatives of thiols and O-acyl derivatives of alcohols or phenols,wherein acyl has a meaning as defined herein. Suitable prodrugs areoften pharmaceutically acceptable ester derivatives convertible bysolvolysis under physiological conditions to the parent carboxylic acid,e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters,benzyl esters, mono- or di-substituted lower alkyl esters, such as theomega-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, the alpha-(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxymethyl ester and the like conventionally used in theart. In addition, amines have been masked as arylcarbonyloxymethylsubstituted derivatives which are cleaved by esterases in vivo releasingthe free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).Moreover, drugs containing an acidic NH group, such as imidazole, imide,indole and the like, have been masked with N-acyloxymethyl groups(Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups havebeen masked as esters and ethers. EP 039,051 (Sloan and Little)discloses Mannich-base hydroxamic acid prodrugs, their preparation anduse. Lower alkyl for the pro-drugs means C₁₋₆-alkyl.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization.

The invention relates in a second aspect to pharmaceutical compositionscomprising a compound of the present invention. The invention thusprovides

-   -   a pharmaceutical composition comprising (i.e. containing or        consisting of) a compound as defined herein and one or more        carriers/excipients;    -   a pharmaceutical composition comprising a therapeutically        effective amount of a compound of formula (I) as defined herein,        and one or more pharmaceutically acceptable carriers/excipients.

The present invention provides a pharmaceutical composition comprising acompound of the present invention and a pharmaceutically acceptablecarrier. The pharmaceutical composition can be formulated for particularroutes of administration such as oral administration, parenteraladministration, and rectal administration, etc. In addition, thepharmaceutical compositions of the present invention can be made up in asolid form (including without limitation capsules, tablets, pills,granules, powders or suppositories), or in a liquid form (includingwithout limitation solutions, suspensions or emulsions). Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifiers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium orcalcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt,or effervescent mixtures; and/or

e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The invention relates in a third aspect to the use of compounds of thepresent invention as pharmaceuticals. Particularly, the compounds offormula (I) have valuable pharmacological properties, as describedhereinbefore and hereinafter. The invention thus provides:

-   -   a compound of the formula (I) as defined herein, as        pharmaceutical/for use as pharmaceutical;    -   a compound of the formula (I) as defined herein, as        medicament/for use as medicament;    -   a compound of the formula (I) as defined herein, for the        treatment of/for use in the treatment of a disorder or a disease        in a subject mediated by the activity of MDM2 and/or MDM4;    -   the use of a compound of formula (I) as defined herein, for the        manufacture of a medicament for the treatment of a disorder or a        disease in a subject mediated by the activity of MDM2 and/or        MDM4;    -   the use of a compound of formula (I) as defined herein, for the        treatment of a disorder or a disease in a subject mediated by        the activity of MDM2 and/or MDM4;    -   the use of a compound of formula (I) as defined herein for the        mediation of the activity of MDM2 and/or MDM4;    -   the use of a compound of formula (I) as defined herein, for the        treatment of a disorder or disease selected from a proliferative        disorder or disease;    -   the use of a compound of formula (I) as defined herein, for the        treatment of a disorder or disease selected from a disorder or        disease involving the immune system;    -   the use of a compound of formula (I) as defined herein, for the        treatment of a proliferative disorder or disease selected from        cancer or tumor diseases, such as benign or malignant tumors, a        sarcoma, such as liposarcoma, rhabdomyosarcoma or bone cancer,        e.g. osteosarcomas, a carcinoma, such as of the brain, kidney,        liver, adrenal gland, bladder, breast, gastric, ovary, colon,        rectum, prostate, pancreas, lung, vagina or thyroid, a        glioblastoma, a multiple myeloma, a gastrointestinal cancer,        especially colon carcinoma or colorectal adenoma, a tumor of the        head and neck, a melanoma, a prostate hyperplasia, a neoplasia,        a neoplasia of epithelial character, a leukemia or a lymphoma,        such as of B- or T-cell origin, and metastases in other organs),        viral infections (e.g. herpes, papilloma, HIV, Kaposi's, viral        hepatitis);    -   the use of a compound of formula (I) as defined herein, for the        treatment of a disorder or disease involving the immune system        selected from autoimmune diseases or immune diseases resulting        due to transplantation (such as rheumatoid arthritis,        graft-versus-host disease, systemic lupus erythematosus,        Sjögren's syndrome, multiple sclerosis, Hashimoto's        thyreoiditis, polymyositis), chronic inflammatory conditions,        such as asthma, osteoarthritis, atherosclerosis, Morbus Crohn or        inflammatory or allergic conditions of the skin, for example        psoriasis, contact dermatitis, atopic dermatitis, alopecia        greata, erythema multiforma, dermatitis herpetiformis,        scleroderma, vitiligo, hypersensitivity angiitis, urticaria,        bullous pemphigoid, pemphigus, epidermolysis bullosa acquisita,        or other inflammatory or allergic conditions of the skin,        hyperproliferative disorders, (e.g. Li-Fraumeni syndrome);    -   a method of modulating of MDM2 and/or MDM4 activity in a        subject, comprising the step of administering to a subject a        therapeutically effective amount of a compound of formula (I) as        defined herein;    -   a method for the treatment of a disorder or a disease mediated        by the activity of MDM2 and/or MDM4 comprising the step of        administering to a subject a therapeutically effective amount of        a compound of formula (I) as defined herein;    -   a method for modifying the activity of MDM2 and/or MDM4 in a        cell, comprising contacting said cell with an effective amount        of a compound of formula (I) as defined herein.

Quite unexpectedly, it has now been found that the compounds of theformula (I) have advantageous pharmacological properties and disturb thebinding interaction (also referred to herein as p53/MDM2 and p53/MDM4interaction or as p53/MDM2 interaction solely) between p53 on the oneside and MDM2 and/or MDM4 or (especially oncogenic) variants thereofwhich still are capable of binding to p53, on the other side.

The efficacy of the compounds of the formula (I) and salts thereof asmodulators affecting the interaction between can be demonstrated asshown in WO 98/01467 (which especially regarding the assays is includedherein by reference) or preferably follows:

Time Resolved Fluorescence Energy Transfer (TR-FRET) Assay

The inhibition of p53-Hdm2 and p53-Hdm4 interactions is measured by timeresolved fluorescence energy transfer (TR-FRET). Fluorescence energytransfer (or Foerster resonance energy transfer) describes an energytransfer between donor and acceptor fluorescent molecules. For thisassay, MDM2 protein (amino acids 2-188) and MDM4 protein (amino acids2-185), tagged with a C-terminal Biotin moiety, are used in combinationwith a Europium labeled streptavidin (Perkin Elmer, Inc., Waltham,Mass., USA) serving as the donor fluorophore. The p53 derived, Cy5labeled peptide Cy5-TFSDLWKLL (p53 aa18-26) is the energy acceptor. Uponexcitation of the donor molecule at 340 nm, binding interaction betweenMDM2 or MDM4 and the p53 peptide induces energy transfer and enhancedresponse at the acceptor emission wavelength at 665 nm. Disruption ofthe formation of the p53-MDM2 or p53-MDM4 complex due to an inhibitormolecule binding to the p53 binding site of MDM2 or MDM4 results inincreased donor emission at 615 nm. The ratiometric FRET assay readoutis calculated from the raw data of the two distinct fluorescence signalsmeasured in time resolved mode (countrate 665 nm/countrate 615 nm×1000).

The test is performed in white 1536w microtiterplates (Greiner Bio-OneGmbH, Frickenhausen, Germany) in a total volume of 3.1 μl by combining100 nl of compounds diluted in 90% DMSO/10% H₂O (3.2% final DMSOconcentration) with 2 μl Europium labeled streptavidin (finalconcentration 2.5 nM) in reaction buffer (PBS, 125 mM NaCl, 0.001%Novexin (consists of carbohydrate polymers (Novexin polymers), designedto increase the solubility and stability of proteins; Novexin Ltd.,Cambridgeshire, United Kingdom), Gelatin 0.01%, 0.2% Pluronic (blockcopolymer from ethylenoxide and propyleneoxide, BASF, Ludwigshafen,Germany), 1 mM DTT), followed by the addition of 0.5 μl MDM2-Bio orMDM4-Bio diluted in assay buffer (final concentration 10 nM). Allow thesolution to pre-incubate for 15 minutes at room temperature, followed byaddition of 0.5 μl Cy5-p53 peptide in assay buffer (final concentration20 nM). Incubate at room temperature for 10 minutes prior to reading theplate. For measurement of samples, an Analyst GT multimode microplatereader (Molecular Devices) with the following settings is used: Dichroicmirror 380 nm, Excitation 330 nm, Emission Donor 615 nm and EmissionAcceptor 665 nm. IC50 values are calculated by curve fitting usingXLfit. If not specified, reagents are purchased from Sigma Chemical Co,St. Louis, Mo., USA.

The present invention also relates to novel aspects of the abovedescribed assays.

Compounds described in the present invention preferably displayinhibition of p53-Hdm2 interaction and p53-Hdm4 interaction at IC50sranging from 0.0003 to 100 μM, preferably from 0.0003 to 25 μM.

Inhibitions of p53-Hdm2 and p53-Hdm4 by representative compounds in thepresent invention are displayed in Table 2 hereinbelow.

Having regard to their inhibitory effect on p53/MDM2 and/or p53/MDM4interaction, compounds of the formula (I) in free or pharmaceuticallyacceptable salt form, are useful in the treatment of conditions whichare mediated by the activity (including normal activity or especiallyoveractivity) of MDM2 and/or MDM4, or variants thereof, respectively, asdescribed, such as proliferative and/or inflammatory conditions, e.g. byactivation of the P53/MDM2 interaction, and/or that are responsive(meaning especially in a therapeutically beneficial way) to inhibitionof the p53/MDM2 interaction, most especially a disease or disorder asmentioned hereinbelow.

Preferred is a compound of the formula (I) for use or the use thereof inthe treatment of a disease or disorder that responds to treatment with acompound of the formula (I), especially selected from a disease that isbased on dysregulation of cell cycle or especially apoptosis: e.g.diseases involving the immune system, e.g. autoimmune diseases or immunediseases resulting due to transplantation (such as rheumatoid arthritis,graft-versus-host disease, systemic lupus erythematosus, Sjögren'ssyndrome, multiple sclerosis, Hashimoto's thyreoiditis, polymyositis),chronic inflammatory conditions, such as asthma, osteoarthritis,atherosclerosis, Morbus Crohn or inflammatory or allergic conditions ofthe skin, for example psoriasis, contact dermatitis, atopic dermatitis,alopecia greata, erythema multiforma, dermatitis herpetiformis,scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullouspemphigoid, pemphigus, epidermolysis bullosa acquisita, or otherinflammatory or allergic conditions of the skin, hyperproliferativedisorders, (e.g. Li-Fraumeni syndrome), cancer or tumor diseases, suchas benign or malignant tumors, a sarcoma, such as liposarcoma,rhabdomyosarcoma or bone cancer, e.g. osteosarcomas, a carcinoma, suchas of the brain, kidney, liver, adrenal gland, bladder, breast, gastric,ovary, colon, rectum, prostate, pancreas, lung, vagina or thyroid, aglioblastoma, a multiple myeloma, a gastrointestinal cancer, especiallycolon carcinoma or colorectal adenoma, a tumor of the head and neck, amelanoma, a prostate hyperplasia, a neoplasia, a neoplasia of epithelialcharacter, a leukemia or a lymphoma, such as of B- or T-cell origin, andmetastases in other organs), viral infections (e.g. herpes, papilloma,HIV, Kaposi's, viral hepatitis) or other diseases, for example those inwhich the p53/MDM2 and/or p53/MDM4 interaction is dysregulated and/orthat are responsive to inhibition of the p53/MDM2 interaction and/orp53/MDM4 interaction.

The invention relates in a fourth aspect to combinations comprising acompound of formula (I) and one or more additional active ingredients.The invention thus provides

-   -   a combination in particular a pharmaceutical combination,        comprising a therapeutically effective amount of a compound of        formula (I) and one or more therapeutically active agents,        particularly antiproliferative agents;    -   a combined pharmaceutical composition, adapted for simultaneous        or sequential administration, comprising a therapeutically        effective amount of a compound of formula (I) as defined herein;        therapeutically effective amount(s) of one or more combination        partners, particularly antiproliferative agents; one or more        pharmaceutically acceptable excepients;    -   a combined pharmaceutical composition as defined herein (i) as        pharmaceutical, (ii) for use in the treatment of a disorder or a        disease mediated by the activity of MDM2 and/or MDM4, (iii) in a        method of treatment of a disorder or a disease mediated by the        activity of MDM2 and/or MDM4.

The invention also relates to the use of a compound of the formula (I)(or a pharmaceutical formulation comprising a compound of the formula(I)) in the treatment of one or more of the diseases mentioned above andbelow where the disease(s) respond or responds (in a beneficial way,e.g. by partial or complete removal of one or more of its symptoms up tocomplete cure or remission) to an inhibition of the p53/MDM2interaction, especially where the involved MDM2 or MDM4 and/or variantshows (e.g. in the context of other regulatory mechanisms, due tooverexpression, to mutation or the like) inadequately high or morehigher than normal activity.

The invention can also relate to the use of a compound of the formula(I) to induce cell cycle deceleration or preferably arrest and/orapoptosis in cells containing p53 or variants thereof that are stillfunctional, for sensitizing cells to one or more additionalpharmaceutically active agents, such as inducers of apoptosis and/or ofcell cycle deceleration or arrest, and to chemoprotection of normalcells through the induction of cell cycle deceleration or arrest priorto treatment with one or more other chemotherapeutic agents, to the usein rendering normal cells resistant to chemotherapeutic agents and/ortreatments, and/or the use in protecting cells from toxic side effectsof chemotherapeutic agents or treatments, such as side effects resultingin mucositis, stomatitis, xerostomia, gastrointestinal disorders and/oralopecia.

All these aspects are preferred embodiments of the present invention.

There are also experiments that can demonstrate the antitumor activityof compounds of the formula (I) in vivo.

For example, female Harlan (Indianapolis, Ind., USA) athymic nu/nu micewith s.c. transplanted human osteosarcoma SJSA-1 tumors can be used todetermine the anti-tumor activity of p53/MDM2 interaction inhibitors. Onday 0, with the animals under peroral Forene®(1-chloro-2,2,2-trifluoroethyldifluormethylether, Abbot, Wiesbaden,Germany) narcosis, 3×10⁶ cells are injected under the skin on theanimals' left flank. When tumors reach a volume of 100 mm³, the mice aredivided at random into groups of 6-8 animals and treatment commences.The treatment is carried out for a 2-3 weeks period with peroral,intravenous or intra-peritoneal administration twice daily (or lessfrequently) of a compound of the formula (I) in a suitable vehicle atdefined doses. The tumors are measured twice a week with a slide gaugeand the volume of the tumors is calculated.

As an alternative to cell line SJSA-1, other cell lines may also be usedin the same manner, for example,

-   -   the HCT116 colon carcinoma cell line (ATCC No. CCL-247);    -   the LNCaP clone FGC prostate carcinoma cell line (ATCC No.        CRL-1740);    -   the RKO colon carcinoma cell line (ATCC No. CRL-2577);    -   the HT1080 fibrosarcoma cell line (ATCC No. CCL-121);    -   the A375 malignant melanoma cell line (ATCC No. CRL-1619),    -   the NCl-H460 large cell lung carcinoma cell line (ATCC No.        HTB-177);    -   the JEG-3 choriocarcinoma (ATCC No. HTB-36)    -   the ZR-75-1 breast ductal carcinoma (ATCC No. CRL-1500)

A compound of the formula (I) may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibittors; mTOR inhibitors,such as RAD001; antineoplastic antimetabolites; platin compounds;compounds targeting/decreasing a protein or lipid kinase activity andfurther anti-angiogenic compounds; compounds which target, decrease orinhibit the activity of a protein or lipid phosphatase; gonadorelinagonists; anti-androgens; methionine aminopeptidase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies, such as HCD122; heparanase inhibitors; inhibitors of Rasoncogenic isoforms; telomerase inhibitors; proteasome inhibitors;compounds used in the treatment of hematologic malignancies, such asfludarabine; compounds which target, decrease or inhibit the activity ofFlt-3, such as PKC412; Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics andAUY922; temozolomide (TEMODAL™); kinesin spindle protein inhibitors,such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; PI3K inhibitors, such asBEZ235; RAF inhibitors, such as RAF265; MEK inhibitors such as ARRY142886 from Array PioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer, leucovorin, EDG binders, antileukemia compounds, ribonucleotidereductase inhibittors, S-adenosylmethionine decarboxylase inhibitors,regulators of apoptosis, antiproliferative antibodies or otherchemotherapeutic compounds. Further, alternatively or in addition theymay be used in combination with other tumor treatment approaches,including surgery, ionizing radiation, photodynamic therapy, implants,e.g. with corticosteroids, hormones, or they may be used asradiosensitizers. Also, in anti-inflammatory and/or antiproliferativetreatment, combination with anti-inflammatory drugs is included.Combination is also possible with antihistamine drug substances,bronchodilatatory drugs, NSAID or antagonists of chemokine receptors.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g. under the trademark AROMASIN.Formestane can be administered, e.g., in the form as it is marketed,e.g. under the trademark LENTARON. Fadrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark AFEMA.Anastrozole can be administered, e.g., in the form as it is marketed,e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, e.g. breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA. Fulvestrant can be formulatedas disclosed in U.S. Pat. No. 4,659,516 or it can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FASLODEX. Acombination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, e.g. breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX™), which canbe formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX. Abarelixcan be formulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO99/17804). Irinotecan can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark CAMPTOSAR. Topotecan can be administered, e.g., in the form asit is marketed, e.g. under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g. in the form as it is marketed, e.g.under the trademark ETOPOPHOS. Teniposide can be administered, e.g. inthe form as it is marketed, e.g. under the trademark VM 26-BRISTOL.Doxorubicin can be administered, e.g. in the form as it is marketed,e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark FARMORUBICIN. Idarubicin can be administered, e.g. in the formas it is marketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark NOVANTRON.

The term “microtubule active compound” relates to microtubulestabilizing, microtubule destabilizing compounds and microtublinpolymerization inhibitors including, but not limited to taxanes, e.g.paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especiallyvinblastine sulfate, vincristine especially vincristine sulfate, andvinorelbine, discodermolides, cochicine and epothilones and derivativesthereof, e.g. epothilone B or D or derivatives thereof. Paclitaxel maybe administered e.g. in the form as it is marketed, e.g. TAXOL™.Docetaxel can be administered, e.g., in the form as it is marketed, e.g.under the trademark TAXOTERE. Vinblastine sulfate can be administered,e.g., in the form as it is marketed, e.g. under the trademark VINBLASTINR.P. Vincristine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FARMISTIN. Discodermolide can beobtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also includedare Epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat.No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247. Especially preferred are Epothilone A and/or B.

The term “alkylating compound” as used herein includes, but is notlimited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNUor Gliadel). Cyclophosphamide can be administered, e.g., in the form asit is marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HOLOXAN.

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark XELODA. Gemcitabine can be administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity”; or a “protein or lipid phosphatase activity”; or “furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, e.g.,

a) compounds targeting, decreasing or inhibiting the activity of theplatelet-derived growth factor-receptors (PDGFR), such as compoundswhich target, decrease or inhibit the activity of PDGFR, especiallycompounds which inhibit the PDGF receptor, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101, SU6668 andGFB-111;b) compounds targeting, decreasing or inhibiting the activity of thefibroblast growth factor-receptors (FGFR);c) compounds targeting, decreasing or inhibiting the activity of theinsulin-like growth factor receptor I (IGF-IR), such as compounds whichtarget, decrease or inhibit the activity of IGF-IR, especially compoundswhich inhibit the kinase activity of IGF-I receptor, such as thosecompounds disclosed in WO 02/092599, or antibodies that target theextracellular domain of IGF-I receptor or its growth factors;d) compounds targeting, decreasing or inhibiting the activity of the Trkreceptor tyrosine kinase family, or ephrin B4 inhibitors;e) compounds targeting, decreasing or inhibiting the activity of the Axlreceptor tyrosine kinase family;f) compounds targeting, decreasing or inhibiting the activity of the Retreceptor tyrosine kinase;g) compounds targeting, decreasing or inhibiting the activity of theKit/SCFR receptor tyrosine kinase, i.e C-kit receptor tyrosinekinases—(part of the PDGFR family), such as compounds which target,decrease or inhibit the activity of the c-Kit receptor tyrosine kinasefamily, especially compounds which inhibit the c-Kit receptor, e.g.imatinib;h) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825)i) compounds targeting, decreasing or inhibiting the activity of membersof the protein kinase C(PKC) and Raf family of serine/threonine kinases,members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK familymembers, and/or members of the cyclin-dependent kinase family (CDK) andare especially those staurosporine derivatives disclosed in U.S. Pat.No. 5,093,330, e.g. midostaurin; examples of further compounds includee.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds such as those disclosed in WO00/09495; FTIs; BEZ235 (a PI3K inhibitor) or AT7519 (CDK inhibitor);j) compounds targeting, decreasing or inhibiting the activity ofprotein-tyrosine kinase inhibitors, such as compounds which target,decrease or inhibit the activity of protein-tyrosine kinase inhibitorsinclude imatinib mesylate (GLEEVEC™) or tyrphostin. A tyrphostin ispreferably a low molecular weight (Mr<1500) compound, or apharmaceutically acceptable salt thereof, especially a compound selectedfrom the benzylidenemalonitrile class or the 5-arylbenzenemalonirile orbisubstrate quinoline class of compounds, more especially any compoundselected from the group consisting of Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin);k) compounds targeting, decreasing or inhibiting the activity of theepidermal growth factor family of receptor tyrosine kinases (EGFR,ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such ascompounds which target, decrease or inhibit the activity of theepidermal growth factor receptor family are especially compounds,proteins or antibodies which inhibit members of the EGF receptortyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 orbind to EGF or EGF related ligands, and are in particular thosecompounds, proteins or monoclonal antibodies generically andspecifically disclosed in WO 97/02266, e.g. the compound of ex. 39, orin EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g. compound knownas CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g.compound ZM105180); e.g. trastuzumab (Herceptin™) cetuximab (Erbitux™),Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5,E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidinederivatives which are disclosed in WO 03/013541; andl) compounds targeting, decreasing or inhibiting the activity of thec-Met receptor, such as compounds which target, decrease or inhibit theactivity of c-Met, especially compounds which inhibit the kinaseactivity of c-Met receptor, or antibodies that target the extracellulardomain of c-Met or bind to HGF;m) compounds targeting, decreasing or inhibiting the activity of PI3K,such as BEZ235 or BKM120;n) compounds targeting, decreasing or inhibiting the activity of thecyclin dependent kinase family, such as PD 0332991.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (THALOMID) and TNP-470.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, e.g. okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes are e.g. retinoicacid, α- γ- or δ-tocopherol or α- γ- or δ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, e.g. Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX™), rofecoxib (VIOXX™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark DIDRONEL. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark BONEFOS. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark SKELID. “Pamidronic acid” can be administered, e.g.in the form as it is marketed, e.g. under the trademark AREDIA.“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FOSAMAX. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONDRANAT. “Risedronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ACTONEL. “Zoledronicacid” can be administered, e.g. in the form as it is marketed, e.g.under the trademark ZOMETA.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune™), everolimus (Certican™ orAfinitor™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88.

The term “biological response modifier” as used herein refers to alymphokine or interferons, e.g. interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g. H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras e.g. a “farnesyl transferaseinhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra).

The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, e.g. telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase are e.g. bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. Bortezomid (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetrazolyle derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors e.g. compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitorse.g. compounds which target, decrease or inhibit anaplastic lymphomakinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,e.g. PKC412, TKI258, midostaurin, a staurosporine derivative, SU11248and MLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90 e.g., 17-allylamino, 17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors. An example HSP90 inhibitor isAUY922.

The term “regulators of apoptosis” as used herein includes, but is notlimited to, compounds targeting, decreasing or inhibiting the activityof Bcl2 family members (such as ABT-263) and IAP family members (such asAEG40826); or inducing apoptosis by known or unknown mechanism(s) ofaction (e.g. TRAIL antibody, DR5 antibody).

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™) rituximab (Rituxan™), PRO64553 (anti-CD40), 2C4Antibody and HCD122 antibody (anti-CD40). By antibodies is meant e.g.intact monoclonal antibodies, polyclonal antibodies, multispecificantibodies formed from at least 2 intact antibodies, and antibodiesfragments so long as they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of theformula (I) can be used in combination with standard leukemia therapies,especially in combination with therapies used for the treatment of AML.In particular, compounds of the formula (I) can be administered incombination with, e.g., farnesyl transferase inhibitors and/or otherdrugs useful for the treatment of AML, such as Daunorubicin, Adriamycin,Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum andPKC412.

The term “antileukemic compounds” includes, for example, Ara-C, apyrimidine analog, which is the 2″-alpha-hydroxy ribose (arabinoside)derivative of deoxycytidine. Also included is the purine analog ofhypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.

Compounds which target, decrease or inhibit activity of histonedeacetylase (HDAC) inhibitors such as sodium butyrate andsuberoylanilide hydroxamic acid (SAHA) inhibit the activity of theenzymes known as histone deacetylases. Specific HDAC inhibitors includeMS275, SAHA, FK228 (formerly FR901228), Trichostatin A, LDH589 disclosedin WO 02/22577 and compounds disclosed in U.S. Pat. No. 6,552,065, inparticular,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl]ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt.

Somatostatin receptor antagonists as used herein refer to compoundswhich target, treat or inhibit the somatostatin receptor such asoctreotide, and SOM230 (pasireotide).

Tumor cell damaging approaches refer to approaches such as ionizingradiation. The term “ionizing radiation” referred to above andhereinafter means ionizing radiation that occurs as eitherelectromagnetic rays (such as X-rays and gamma rays) or particles (suchas alpha and beta particles). Ionizing radiation is provided in, but notlimited to, radiation therapy and is known in the art. See Hellman,Principles of Radiation Therapy, Cancer, in Principles and Practice ofOncology, Devita et al., Eds., 4^(th) Edition, Vol. 1, pp. 248-275(1993).

The term “EDG binders” as used herein refers a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720.

The term “ribonucleotide reductase inhibitors” refers to pyrimidine orpurine nucleoside analogs including, but not limited to, fludarabineand/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil,cladribine, 6-mercaptopurine (especially in combination with ara-Cagainst ALL) and/or pentostatin. Ribonucleotide reductase inhibitors areespecially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives,such as PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned inNandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).

The term “S-adenosylmethionine decarboxylase inhibitors” as used hereinincludes, but is not limited to the compounds disclosed in U.S. Pat. No.5,461,076.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF disclosed in WO 98/35958, e.g.1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof, e.g. the succinate, or in WO 00/09495, WO00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; thoseas described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218(1999); Yuan et al., Proc Natl Acad Sci USA, Vol. 93, pp. 14765-14770(1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209-3214 (1998); andMordenti et al., Toxicol Pathol, Vol. 27, No. 1, pp. 14-21 (1999); in WO00/37502 and WO 94/10202; ANGIOSTATIN, described by O'Reilly et al.,Cell, Vol. 79, pp. 315-328 (1994); ENDOSTATIN, described by O'Reilly etal., Cell, Vol. 88, pp. 277-285 (1997); anthranilic acid amides; ZD4190;ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies oranti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g.Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as e.g. VISUDYNE™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone.hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such as e.g.fluocinolone, dexamethasone.

“Other chemotherapeutic compounds” include, but are not limited to,plant alkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The structure of the active compounds identified by code nos., genericor trade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

None of the quotations of references made within the present disclosureis to be understood as an admission that the references cited are priorart that would negatively affect the patentability of the presentinvention.

Pharmaceutical Formulations, Uses and Methods

The above-mentioned compounds, which can be used in combination with acompound of the formula (I), can be prepared and administered asdescribed in the art, such as in the documents cited above.

The invention also provides a pharmaceutical preparation, comprising acompound of the formula (I) as defined herein, and/or an N-oxide or atautomer thereof, and/or a pharmaceutically acceptable salt of such acompound, or a hydrate or solvate thereof (all referred to often as “acompound of the formula (I)” merely herein), and at least onepharmaceutically acceptable carrier.

A compound of the formula (I) can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic (including prophylactic) compounds being staggered or givenindependently of one another, or the combined administration of fixedcombinations and one or more other therapeutic compounds. A compound ofthe formula (I) can besides or in addition be administered especiallyfor tumor therapy in combination with chemotherapy, radiotherapy,immunotherapy, phototherapy, surgical intervention, or a combination ofthese. Long-term therapy is equally possible as is adjuvant therapy inthe context of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

The dosage of the active ingredient depends upon a variety of factorsincluding type, species, age, weight, sex and medical condition of thepatient; the severity of the condition to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular compound employed. A physician, clinician or veterinarian ofordinary skill can readily determine and prescribe the effective amountof the drug required to prevent, counter or arrest the progress of thecondition. Optimal precision in achieving concentration of drug withinthe range that yields efficacy requires a regimen based on the kineticsof the drug's availability to target sites. This involves aconsideration of the distribution, equilibrium, and elimination of adrug.

The dose of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof to be administered to warm-blooded animals, forexample humans of approximately 70 kg body weight, is preferably fromapproximately 3 mg to approximately 15 g, more preferably fromapproximately 10 mg to approximately 3 g, yet more preferably fromapproximately 50 mg to 1.5 g per person per day, undivided in 1 dose ordivided preferably into 2 to 4, e.g. 2 or 3, single doses which may, forexample, be of the same size. Usually, children receive half of theadult dose.

The compounds of the formula (I) may be administered by any conventionalroute, in particular parenterally, for example in the form of injectablesolutions or suspensions, enterally, e.g. orally, for example in theform of tablets or capsules, topically, e.g. in the form of lotions,gels, ointments or creams, or in a nasal or a suppository form. Topicaladministration is e.g. to the skin. A further form of topicaladministration is to the eye. Pharmaceutical compositions comprising acompound of the invention in association with at least onepharmaceutical acceptable carrier or diluent may be manufactured inconventional manner by mixing with a pharmaceutically acceptable carrieror diluent.

The invention relates also to pharmaceutical compositions comprising aneffective amount, especially an amount effective in the treatment of oneof the above-mentioned disorders, of a compound of the formula (I)and/or an N-oxide or a tautomer thereof, and/or a pharmaceuticallyacceptable salt thereof, together with one or more pharmaceuticallyacceptable carriers that are suitable for topical, enteral, for exampleoral or rectal, or parenteral administration and that may be inorganicor organic, solid or liquid. There can be used for oral administrationespecially tablets or gelatin capsules that comprise the activeingredient together with diluents, for example lactose, dextrose,mannitol, and/or glycerol, and/or lubricants and/or polyethylene glycol.Tablets may also comprise binders, for example magnesium aluminumsilicate, starches, such as corn, wheat or rice starch, gelatin,methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and, if desired, disintegrators, for examplestarches, agar, alginic acid or a salt thereof, such as sodium alginate,and/or effervescent mixtures, or adsorbents, dyes, flavorings andsweeteners. It is also possible to use the pharmacologically activecompounds of the present invention in the form of parenterallyadministrable compositions or in the form of infusion solutions. Thepharmaceutical compositions may be sterilized and/or may compriseexcipients, for example preservatives, stabilisers, wetting compoundsand/or emulsifiers, solubilisers, salts for regulating the osmoticpressure and/or buffers. The present pharmaceutical compositions, whichmay, if desired, comprise other pharmacologically active substances areprepared in a manner known per se, for example by means of conventionalmixing, granulating, confectionning, dissolving or lyophilisingprocesses, and comprise approximately from 1% to 99%, especially fromapproximately 1% to approximately 20%, active ingredient(s).

Additionally, the present invention provides a compound of the formula(I), and/or an N-oxide or a tautomer thereof, and/or a pharmaceuticallyacceptable salt thereof, for use in a method for the treatment of thehuman or animal body, especially for the treatment of a diseasementioned herein, most especially in a patient requiring such treatment.

The present invention also relates to the use of a compound of theformula (I) and/or an N-oxide or a tautomer thereof, and/or apharmaceutically acceptable salt of such a compound, for the preparationof a medicament for the treatment especially of a proliferative disease,especially cancer.

Furthermore, the invention relates to a method for the treatment of aproliferative disease which responds to an inhibition of the p53/MDM2interaction, which comprises administering a compound of the formula(I), and/or an N-oxide or a tautomer thereof, and/or a pharmaceuticallyacceptable salt thereof, wherein the radicals and symbols have themeanings as defined above, to a warm-blooded animal requiring suchtreatment, especially in a quantity effective against said diseaseand/or capable of inhibiting the p53/MDM2 interaction in saidwarm-blooded animal.

Furthermore, the invention relates to a pharmaceutical composition fortreatment of solid or liquid tumors in warm-blooded animals, includinghumans, comprising an antiproliferativly effective dose of a compound ofthe formula (I) as described above or a pharmaceutically acceptable saltof such a compound together with a pharmaceutical carrier.

The invention relates in a fifth aspect to the manufacture of a compoundof formula (I). The compounds of formula (I) or salts thereof areprepared in accordance with processes known per se (see references citedabove), though not previously described for the manufacture of thecompounds of the formula (I).

Synthesis of Compounds of the Formula (I)

Typically, the compounds of the formula (I) can be prepared according tothe Schemes provided below.

Scheme A illustrates one method of preparing compounds of the inventionmainly according to a modified published procedure (Venkov, A. andMolloy, N. Synthesis 1982, 3, 216-217).

The benzaldehyde derivative is used in a Grignard type reactiontypically in THF and typically at −78° C. to obtain the correspondingbenzylalcohol. The alcohol derivative is oxidized by pyridiniumdichromate (PDC) or other oxidizing reagents such as manganese dioxide.

The methyl acetate group is introduced using malonic acid tert-butylester methyl ester and a strong base typically NaH and using heat,typically the reaction is heated to 60° C. in an aprotic solvent such asDMSO. In a second step, the crude product was treated with typicallywith trifluoroacetic acid in an organic solvent such as DCM.Saponification was done using LiOH in typically used methanol/water(2:1), typically at room temperature. After acidification with 2 M HCl,the precipitate was collected and extracted with organic solvents.

To a suspension of the free acid typically in EtOH, or other alcoholsuch as methanol, was added NaBH₄, typically at room temperature. Tothis solution the thionyl chloride was added, typically at 0° C. and thereaction is stirred at r.t.

Benzylchlorides were treated typically under basic conditions with DIPEAor triethyl amine, in DCM or other organic solvents such as dioxan, DMF,DMSO and substituted anilines at room temperature and then evaporated todryness. To a solution of the resulting residue in acetic acid, wasadded sulfuric acid at RT and the mixture was heated at 80° C., stirredfor 1 h then cooled to RT, and concentrated under vacuum. The nitrogroup was reduced by treating the starting material with tin chloridetypically in EtOH at RT. The slurry was heated at 80° C. and vigorouslystirred 30 min.

The resulting aniline was further substituted with different acidchloride (acylation), e.g. propionyl chloride, or with differentaldehydes or ketones using reductive amination conditions (AcOH,NaBH(OAc)₃, DCM, RT) to receive different alkylated products.

(3,4-Dialkoxy-phenyl)-acetic acid ethyl ester was treated withdichloro-methoxy-methane in typically DCM by slowly added SnCl₄ (1Msolution in DCM), over typically 30 minutes. After the completeaddition, the reaction was typically stirred at 0° C. for 1.5 hrs. Thechiral auxiliar group was added following the procedure from Davis etal. (Frank A. Davis, Pradyumna K. Mohanty; J. Org. Chem., 2002, 67, 4,1290) using typically a Lewis acid such as Ti(OEt)₄ and typically anaprotic solvent such as DCM.

The enantioselevtive addition of the aryl group followed the procedurefrom Oi et al (S. Oi, M. Moro, H. Fukurhara, T. Kawanishi, Y. Inoue,Tetrahedron, 59, 2003, 4351). The tin reagent was added to a solution ofstarting material (sulfoximine) in an organic solvent such as THF,dioxane or acetonitrile, but typically THF in the presence of a rhodiumcatalyst, such as bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate. The reaction is carriedout typically at elevated temperature such as 60° C. Other reagents thanthe tin reagents can be utilized such as the corresponding borate salts.Deprotection od the sulfoxamine group was typically done under acidicconditions using acids such as HCl (e.g. 1.25 M in ethanol) in anorganic solvent such as an alcohol, typically methanol. The free aminewas evaporated to dryness, re-dissolved in typically methanol and a baseis added, typically triethylamine and the reaction is stirred attypically room temperature.

The cross-coupling reaction is carried out following Buchwald'scondition for the C—N amidation reaction, typically following Buchwaldliterature procedure (A. Klapars, Xiaohua Huang, S. L. Buchwald; J. Am.Chem. Soc., 2002, 124, 7421). Under an inert argon atmosphere and usingdegassed aprotic solvents encompassing toluene, dioxane, THF and DMF,but typically dioxane, the starting materials (isoquinolinone and arylhalide) are mixed in the presence of a copper source, such as Cu powder,CuI, CuCN, Cu₂O, CuCl₂, but typically CuI and an diamine ligand, such asethylenediamine, or other 1,2-diamine ligands, but typicallytrans-1,2-cyclohexanediamine in the presence of a base, such as K₃PO₄,K₂CO₃ or CsCO₃, but typically K₃PO₄. The reaction is heated to typically100-110° C. and stirred for 4 to 16 hours depending the progress of thereaction.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known to those skilled in theart.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, and the like.

The following applies in general to all processes mentioned hereinbefore and hereinafter.

All the above-mentioned process steps can be carried out under reactionconditions that are known to those skilled in the art, including thosementioned specifically, in the absence or, customarily, in the presenceof solvents or diluents, including, for example, solvents or diluentsthat are inert towards the reagents used and dissolve them, in theabsence or presence of catalysts, condensation or neutralizing agents,for example ion exchangers, such as cation exchangers, e.g. in the H+form, depending on the nature of the reaction and/or of the reactants atreduced, normal or elevated temperature, for example in a temperaturerange of from about −100° C. to about 190° C., including, for example,from approximately −80° C. to approximately 150° C., for example at from−80 to −60° C., at room temperature, at from −20 to 40° C. or at refluxtemperature, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described herein above.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol, ethanol or 1- or 2-propanol, nitriles, such asacetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, methycyclohexane, or mixtures of those solvents, for exampleaqueous solutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4^(th) Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21).

In another embodiment of the invention there is provided a compound ofintermediate 75.6 below:

In another embodiment of the invention there is provided an intermediatecompound of the following formula as described in synthetic scheme C:

-   -   wherein R′, R¹, n and X are as described herein. Preferably, in        said intermediate, R′ is independently selected from        C₁-C₆-alkyl-, n is O and X is halo. In a particular embodiment,        the intermediate has the following stereochemistry:

ABBREVIATIONS

-   Ac acetyl-   AcOEt ethyl acetate-   AcOH acetic acid-   aq. aqueous-   API-MS Atmospheric Pressure Ionization Mass Spectroscopy-   BH₃.THF borane tetrahydrofuran complex-   Boc t-butoxycarbonyl-   brine saturated aqueous sodium chloride solution at RT-   ^(t)Bu t-butyl-   DCl₃ deuteriated chloroform-   CD₃OD deuteriated methanol-   Celite trademark of Celite Corp. (World Minerals Inc.), Santa    Barbara, Calif., USA, for filtering aid based on kieselguhr-   CHCl₃ chloroform-   conc. concentrated-   Cs₂CO₃ cesium carbonate-   CuI copper(I) iodide-   Cu₂O copper(I) oxide-   DCM dichloromethane-   DIPEA diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DTAD di-t-butyl azodicarboxylate-   equiv. equivalent-   Et ethyl-   Et₃N triethylamine-   Et₂O diethyl ether-   EtOH ethanol-   Fe iron metal-   g gramm(s)-   h hour(s)-   HATU    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphat-   HCl hydrogen chloride-   HNO₃ nitric acid-   HPLC high-pressure liquid chromatography-   H₂SO₄ sulfuric acid-   iPr isopropyl-   K₂CO₃ potassium carbonate-   KOH potassium hydroxide-   K₃PO₄ potassium phosphate-   LC-MS liquid chromatography mass spectroscopy-   LiBH₄ lithium borohydride-   LiOH lithium hydroxide-   M molar-   Me methyl-   MeCN acetonitrile-   mg milligram(s)-   MeI methyl iodide-   MeOH methanol-   min minute(s)-   ml milliliter(s)-   mmol millimole(s)-   MnO₂ manganese(IV) oxide-   MS mass spectrometry-   NaBH₄ sodium borohydride-   NaBH₃CN sodium cyanoborohydride-   NaBH(OAc)₃ sodium triacetoxyborohydride-   Na₂CO₃ sodium carbonate-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   NaN₃ sodium azide-   NaOCN sodium cyanate-   NaOH sodium hydroxide-   Na₂SO₄ sodium sulfate-   NH₃ ammoniac-   NH₄Cl ammonium chloride-   NMM 4-methylmorpholine-   NMR nuclear magnetic resonance-   PDC pyridinium dichromate-   Pd/C palladium over charcoal-   PdCl₂(PPh₃)₂ dichlorobis(triphenylphosphine)-palladium (II)-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium-   Ph phenyl-   PPh₃ triphenylphosphine-   prep-HPLC preparative high-pressure liquid chromatography-   PTSA p-toluenesulfonic acid-   quant. quantitative-   R_(F) retention factor-   RT room temperature-   SiO₂ silica-   SnCl₂ stannous chloride or Tin(II) chloride-   SnCl₄ Tin(IV) chloride-   SOCl₂ thionyl chloride-   TBDMSCl tert-butyldimethylsilyl chloride-   TBME tert-butyl-dimethyl ether-   TFA trifluoroacetic acid-   THF tetrahydrofurane-   Ti(OEt)₄ titanium(IV) ethoxide-   Ti(OiPr)₄ titanium(IV) isopropoxide-   TLC thin layer chromatography-   t_(Ret) retention time    General Methods.

¹H-NMR measurements were performed on a Bruker Ultrashield™400 (400MHz), Bruker Ultrashield™ 600 (600 MHz) or a 500 MHz DRX BrukerCryoProbe (500 MHz) spectrometer using or not trimethylsilane as aninternal standard. Chemical shifts (d-values) are reported in ppmdownfield from tetramethylsilane, coupling constants (J) are given inHz, spectra splitting pattern are designated as singulet (s), doublet(d), doublet doublet (dd), triplet (t), quadruplet (q), multiplet ormore overlapping signals (m), broad signal (br). Solvents are given inparentheses.

prep-HPLC purifications were performed using optimized gradient elution(CH₃CN/water with 0.1% TFA) with a Waters HPLC prep-system equipped witha UV detector Waters 2487 Dual Absorbance Detector, a MS detector WatersmicromassZQ, and a reversed phase column SunFire™ Prep, C18 OBD, 100×30mm, 5 m, or 100×19 mm, 5 m. Generally products were obtained as TFAsalts after lyophilization.

TLC were performed with precoated silica gel 60 F₂₅₄ glass plates(Merck, Darmstadt, Germany) using the respective named solvent systems.Visualization was generally done by UV light (254 nm).

LC-MS spectra were recorded on a Waters 2795 Alliance HT instrument witha Sunfire™ C18, 4.6×20 mm, 3.5 m column, eluting with a linear gradientof 5 to 100% MeCN (+0.1% TFA) in water (+0.1% TFA) in 4 min with a flowrate of 3 ml/min at 45° C., with positive ion electrospray ionization(Micromass ZQ Detector).

API-MS spectra were recorded on an Agilent 1100 instrument with aAscentis Expresse™ C18, 2.1×30 mm, 2.7 m column, eluting with a lineargradient of 2 to 98% MeCN (+0.04% formic acid) in water (+0.05% formicacid+0.05% of a 7.5 M aqueous ammonium acetate solution) in 1.7 min witha flow rate of 1.2 ml/min at 50° C., with positive and/or negative ionelectrospray ionization (ZMD Detector).

[M+H]⁺and [M−H]⁻ refer to monoisotopic molecular weights.

HPLC retention times (^(X)t_(Ret)) were reported in min and wererecorded using the following conditions:

Retention times for system A (^(A)t_(Ret)) were measured with a Waters2795 Alliance HT instrument equipped with a Waters 2996 Photodiode ArrayDetector (PDA MaxPlot detection at 210.0 nm to 400.0 nm) and a MicromassZQ Detector (positive ion electrospray ionization detection), elutingwith a linear gradient of 5 to 100% MeCN (+0.1% TFA) in water (+0.1%TFA) in 4 min with a flow rate of 3 ml/min at 45° C. The column was aSunfire™ C18, 4.6×20 mm, 3.5 m.

Retention times for system B (^(B)t_(Ret)) were measured with a Waters2695 Alliance HT instrument equipped with a Waters 2996 Photodiode ArrayDetector (PDA MaxPlot detection at 210.0 nm to 400.0 nm), eluting with alinear gradient of 5 to 100% MeCN in water (+0.1% TFA) in 4 min with aflow rate of 3 ml/min at 35° C. The column was a Sunfire™ C18, 4.6×20mm, 3.5 m.

Retention times for system C (^(C)t_(Ret)) were measured with an Agilent1100 instrument equipped with an Agilent 1100 series Photodiode ArrayDetector (PDA MaxPlot detection at 210.0 nm to 400.0 nm), eluting withan isocratic of 40% MeCN in water (+5 mM ammonium formate) for 1 minthen a gradient of 40 to 60% MeCN in water (+5 mM ammonium formate) in 7min with a flow rate of 2 ml/min at 40° C. The column was a Sunfire™C18, 4.6×50 mm, 5 m.

Retention times for system D (^(D)t_(Ret)) were measured with a Watersinstrument equipped with a Waters Acquity HPLC PDA Detector (detectionat 120 nm to 1200.0 nm), eluting with an isocratic from 0-1.40 min of 2to 98% MeCN(0.04% HCOOH) in water (+0.05% HCOOH+0.05% Ammonium Acetate),1.40-2.15 min. 98% MeCN(0.04% HCOOH), 2.15-2.19 min of 98% to 2%MeCN(+0.04% HCOOH) then 2.19-2.20 min of 2% MeCN(+0.04% HCOOH) with aflow rate of 1.2 ml/min at 50° C. The column was a Acquity HSS T3,2.1×50 mm, 1.8 μm

Retention times for system E (^(E)t_(Ret)) were measured with a Agilent1100 instrument equipped with an Agilent 1100 series Dioden ArrayDetector (DAD detection at 215 nm), eluting with an isocratic from 0-5.0min of 2 to 100% MeCN(0.1% TFA) in water (+0.1% TFA), 5.0-6.5 min. 100%MeCN(0.1% TFA) then 6.5-7.0 min of 100% to 2% MeCN(+0.1% TFA) with aflow rate of 1.0 ml/min at 30° C. The column was a Nucleosil 100-3 C18HD, 4.0×70 mm

Retention times for system F (^(F)t_(Ret)) were measured with a Watersinstrument equipped with a Waters Acquity HPLC PDA Detector (PDA MaxPlotdetection at 210.0 nm to 400.0 nm)), eluting with an isocratic from0.1-1.60 min of 2 to 100% MeCN(0.05% HCOOH) in water (+0.05% HCOOH),1.60-2.0 min. 100% MeCN(0.05% HCOOH) then 2.0-2.0 min of 100% to 2%MeCN(+0.05% HCOOH) with a flow rate of 1.0 ml/min at 40° C. The columnwas a Acquity BEH C18, 2.1×50 mm, 1.7 m.

Retention times for system G (^(G)t_(Ret)) were measured with a Agilent1100 instrument equipped with an Agilent 1100 series Dioden ArrayDetector (DAD detection at 215 nm), eluting with an isocratic from 0-7.0min of 2 to 100% MeCN(0.1% TFA) in water (+0.1% TFA), 7.0-9.0 min. 100%MeCN(0.1% TFA) then 9.0-10.0 min of 100% to 2% MeCN(+0.1% TFA) with aflow rate of 1.0 ml/min at 30° C. The column was a Nucleosil 100-3 C18HD, 4.0×125 mm (Macherey-Nagel).

Retention times for system H (^(H)t_(Ret)) were measured with a Watersinstrument equipped with a Waters Acquity HPLC PDA Detector (detectionat 120 nm to 1200.0 nm), eluting with an isocratic from 0-3.0 min of 10to 95% MeCN(0.1% HCOOH) in water (+0.1% HCOOH), 3.0-4.0 min. 95%MeCN(0.1% HCOOH) with a flow rate of 1.2 ml/min at 50° C. The column wasa Acquity HSS T3 2.1×50 mm, 1.8 m.

Retention times for system I (^(I)t_(Ret)) were measured with a Agilent1100 instrument equipped with an Agilent 1100 series Dioden ArrayDetector (DAD detection at 215 nm), eluting with an isocratic from 0-8.0min of 2 to 100% MeCN(0.1% TFA) in water (+0.1% TFA), 8.0-10.0 min. 100%MeCN(0.1% TFA), 10.0-11.0 min of 100% to 2% MeCN(+0.1 TFA) then11.0-13.0 min of 2% MeCN(+0.1% TFA) with a flow rate of 2.0 ml/min at25° C. The column was a Chromolith Performance RP-18e, 4.6×100 mm(Merck)

Retention times for system J (^(J)t_(Ret)) were measured with a ThermoFinnigan instrument equipped with an UV 6000LP Photodiode Array Detector(DAD detection at 218 nm), eluting with an isocratic from 0-8.0 min of 2to 100% MeCN(0.1% HCOOH) in water (+0.1% HCOOH), 8.0-10.0 min. 100%MeCN(0.1% HCOOH) then 10.0-11.0 min of 100% to 2% MeCN(+0.1% HCOOH) witha flow rate of 2.0 ml/min at 30° C. The column was a ChromolithPerformance RP-18e, 4.6×100 mm(Merck)

Retention times for system K (^(K)t_(Ret)) were measured with a Agilent1100 instrument equipped with an Agilent 1100 series Dioden ArrayDetector (DAD detection at 215 nm), eluting with an isocratic from 0-7.0min of 2 to 100% MeCN(0.1% TFA) in water (+0.1% TFA), 7.0-9.0 min. 100%MeCN(0.1% TFA) then 9.0-10.0 min of 100% to 2% MeCN(+0.1% TFA) with aflow rate of 1.0 ml/min at 30° C. The column was a Nucleosil 100-3 C18HD, 4.0×125 mm

Retention times for system L (^(L)t_(Ret)) were measured with a Agilent1100 instrument equipped with an Agilent 1100 series Dioden ArrayDetector (DAD detection at 215 nm), eluting with an isocratic from 0-5.0min of 20 to 100% MeCN(0.1% TFA) in water (+0.1% TFA), 5.0-6.5 min. 100%MeCN(0.1% TFA) then 6.5-7.0 min of 100% to 20% MeCN(+0.1% TFA) with aflow rate of 1.0 ml/min at 30° C. The column was a Nucleosil 100-3 C18HD, 4.0×125 mm

Retention times for system M (^(M)t_(Ret)) were measured with a Watersinstrument equipped with a Waters Acquity HPLC PDA Detector (detectionat 120 nm to 1200.0 nm), eluting with an isocratic from 0-1.40 min of 2to 98% MeCN(0.04% HCOOH) in water (+0.05% HCOOH+0.05% Ammonium Acetate),1.40-2.15 min. 98% MeCN(0.04% HCOOH), 2.15-2.19 min of 98% to 2%MeCN(+0.04% HCOOH) then 2.19-2.20 min of 2% MeCN(+0.04% HCOOH) with aflow rate of 1.2 ml/min at 50° C. The column was a Acquity HSS T3,2.1×50 mm, 1.8 μm

Retention times for system N (^(N)t_(Ret)) were measured with a Agilent1100 instrument equipped with an Agilent 1100 series Dioden ArrayDetector (DAD detection at 215 nm-350 nm), eluting with an isocraticfrom 0-1.40 min of 2 to 98% MeCN(0.04% HCOOH) in water (+0.5%HCOOH+0.05% Ammonium Acetate), 1.40-2.15 min. 98% MeCN(0.04% HCOOH),2.15-2.19 min of 98% to 2% MeCN(+0.04% HCOOH) then 2.19-2.20 min of 2%MeCN(+0.04% HCOOH) with a flow rate of 1.2 ml/min at 50° C. The columnwas an Acentis Express C18, 2.1×30 mm, 2.7 μm

Retention times for system O (^(O)t_(Ret)) were measured with a Waters2690 instrument equipped with an Waters 996 series Photodiode ArrayDetector (detection at 215 nm and 254 nm), eluting with an isocraticfrom 1.0-11.0 min of 2 to 100% MeCN(0.1% TFA) in water (+0.1% TFA) then11.0-13.0 min of 100% MeCN(+0.1% TFA) with a flow rate of 1.0 ml/min at35° C. The column was Column Engineering, Inc., Matrix C18 4.6×150 mm(Lot#205), 3.0 μm

EXAMPLES

The following examples serve to illustrate the invention withoutlimiting the scope thereof. Note that in some cases compounds mentionedas intermediates are also compounds of the formula I according to theinvention (it is then mentioned that the compounds fall under formulaI). Names of each examples or intermediates were automatically generatedusing AutoNom 2000 from IsisDraw. Where no specific source is indicated,starting materials and solvents are obtainable from customary suppliers,such as Sigma-Aldrich, Fluka, Alfa Aesar, Merck, or from providersindicated specifically. Abbreviations.

Example 17-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

Intermediate 1.3 (41.4 mg, 0.16 mmol) was added to a solution ofIntermediate 1.4 (40 mg, 0.16 mmol) in DCM (1 ml) at RT and theresulting yellow slurry was stirred for 1 h. Methanesulfonic acid (0.10ml, 1.6 mmol) was added drop wise and the mixture was further stirredfor 15 min at RT. The reaction mixture was concentrated under vacuum andthe resulting residue was purified by reverse phase prep-HPLC (Waterssystem) to yield the title compound (TFA salt, 10 mg, 0.017 mmol, 10%).HPLC: ^(A)t_(Ret)=2.03 min; API-MS: m/z 480.6 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃): 0.93-1.03 (2t, J=7.5, 3H, mixture of diastereoisomers),1.25-1.34 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.57-1.85 (m,2H), 3.12 (s, 6H), 3.79 (d, J=19.8, 1H), 3.86-3.95 (m, 4H), 4.17-4.26(m, 1H), 5.74 (s, 1H), 6.68-6.74 (m, 2H), 7.06-7.11 (m, 2H), 7.18-7.24(m, 2H), 7.26-7.32 (m, 4H).

Intermediate 1.1: [4-((R)-sec-Butoxy)-3-methoxy-phenyl]-acetic acidethyl ester

To a solution of (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester(700 mg, 3.33 mmol) in DCM (40 ml) were successively added(S)-butan-2-ol (0.37 ml, 4.0 mmol), supported PPh₃ (loading of 1.52mmol/g, 4.38 g, 6.66 mmol) and DTAD (1.15 g, 5.0 mmol). The reactionmixture was shaken at RT for 3 h, then filtered and the resin was washedwith DCM. The filtrate was evaporated to dryness and the resultingresidue was purified by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, heptane/TBME 95:5→1:1) to yieldthe title compound (818 mg, 3.07 mmol, 92%) as a colorless oil. TLC:R_(F)=0.85 (heptane/DCM/TBME 1:1:2); HPLC: ^(B)t_(Ret)=2.46 min; API-MS:m/z 267.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃): 1.00 (t, J=7.5, 3H), 1.28 (t,J=7.1, 3H), 1.33 (d, J=6.1, 3H), 1.60-1.70 (m, 1H), 1.77-1.89 (m, 1H),3.56 (s, 2H), 3.86 (s, 3H), 4.17 (q, J=7.1, 2H), 4.25 (sxt, J=6.1, 1H),6.79 (dd, J=8.3, 2.0, 1H), 6.83-6.87 (m, 2H).

Intermediate 1.2: [4-((R)-sec-Butoxy)-3-methoxy-phenyl]-acetic acid

A mixture of Intermediate 1.1 (818 mg, 3.07 mmol) in EtOH (8 ml) andwater (2 ml) was treated with LiOH monohydrate (387 mg, 9.21 mmol) at RTand stirred for 1 h. The reaction mixture was neutralized by theaddition of HCl 0.5 M in water then extracted with DCM. The organicfraction was dried over Na₂SO₄, filtered and evaporated to dryness toyield the title compound (740 mg, 3.07 mmol, quant) as a yellow oil,which was used in the next step without further purification. HPLC:^(B)t_(Ret)=1.80 min; API-MS: m/z 237.2 [M−H]⁺; ¹H NMR (400 MHz, CDCl₃):1.00 (t, J=7.5, 3H), 1.33 (d, J=6.1, 3H), 1.58-1.70 (m, 1H), 1.77-1.89(m, 1H), 3.60 (s, 2H), 3.86 (s, 3H), 4.21-4.31 (m, 1H), 6.78-6.88 (m,3H).

Intermediate 1.3: [4-((R)-sec-Butoxy)-3-methoxy-phenyl]-acetyl chloride

To a solution of Intermediate 1.2 (372 mg, 1.56 mmol) in DCM (15 ml)were successively added oxalylchloride (0.2 ml, 2.3 mmol) and acatalytic amount of DMF (0.012 ml, 0.16 mmol) at 0° C. (ice bath). Thereaction mixture was stirred at 0° C. for 30 min then evaporated todryness under vacuum to yield the crude title compound (401 mg, 1.56mmol, quant.) as an orange oil which was used in the next step withoutfurther purification.

Intermediate 1.4:N-[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-N′,N′-dimethyl-benzene-1,4-diamine

To a mixture of 4-chloro-benzaldehyde (1.55 g, 11.0 mmol) andN,N-dimethyl-benzene-1,4-diamine (1.5 g, 11.0 mmol) in EtOH (15 ml) wasadded a catalytic amount of AcOH (0.063 ml, 1.1 mmol) at RT. Thereaction mixture was heated at reflux and stirred for 14 h during whichtime precipitation took place. After cooling to RT, the slurry wasfiltered and washed with heptane. The solid was collected and driedunder high vacuum to yield the title compound (2.09 g, 8.08 mmol, 73%)as a brownish solid. ¹H NMR (400 MHz, CDCl₃): 3.01 (s, 6H), 6.78 (m,2H), 7.29 (m, 2H), 7.44 (m, 2H), 7.84 (m, 2H), 8.49 (s, 1H).

Example 2

Compounds 2aa to 2bj were obtained analogously to Example 1 from variousphenyl-acetyl chlorides (prepared analogously to Intermediate 1.3) andimines (prepared from commercially available aldehydes and anilinesanalogously to Intermediate 1.4).

# Structure Name/HPLC/MS 2aa

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.88;API-MS: m/z 465.3 [M + H]⁺. 2ab

1-(3,4-Difluoro-phenyl)-6,7-diethoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.51;API-MS: m/z 454.3 [M + H]⁺. 2ac

4-[1-(4-Chloro-phenyl)-6,7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzonitrile. HPLC: ^(A)t_(Ret) = 2.60; API-MS: m/z447.1 [M + H]⁺. 2ad

1-(4-Chloro-phenyl)-6,7-diethoxy-2-(5-methyl-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.67;API-MS: m/z 437.2 [M + H]⁺. 2ae

2-Benzofuran-5-yl-1-(4-chloro-phenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.67; API-MS: m/z462.1 [M + H]⁺. 2am

1-(4-Chloro-phenyl)-6,7-diethoxy-2-(6-methyl-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.72;API-MS: m/z 437.2 [M + H]⁺. 2an

1-(4-Chloro-phenyl)-2-(4-dimethylamino-2-methoxy-phenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret)= 1.96; LC-MS: m/z 496.2 [M + H]⁺. 2ao

1-(4-Chloro-phenyl)-6,7-diethoxy-2-(4-morpholin-4-yl-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.33;LC-MS: m/z 507.2 [M + H]⁺. 2ap

1-(4-Chloro-phenyl)-6,7-diethoxy-2-(2-methoxy-4-morpholin-4-yl-phenyl)-1,4-dihydro-2H-isoquinolin-3- one. HPLC:^(A)t_(Ret) = 2.36; LC-MS: m/z 537.2 [M + H]⁺. 2aq

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(3,4-dimethyl-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) =2.96; API-MS: m/z 465.6 [M + H]⁺. 2ar

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(2,4-dimethyl-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) =2.97; API-MS: m/z 465.6 [M + H]⁺. 2as

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(2-methoxy-5-methyl-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.86; API-MS: m/z 481.9 [M + H]⁺. 2at

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-methoxy-2-methyl-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.80; API-MS: m/z 481.6 [M + H]⁺. 2au

7-((R)-sec-Butoxy)-2-(2-chloro-4-methyl-phenyl)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin- 3-one. HPLC:^(A)t_(Ret) = 3.00; API-MS: m/z 485.9 [M + H]⁺. 2av

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.74; API-MS: m/z 497.7 [M + H]⁺. 2aw

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(3,4-dichloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) =3.14; API-MS: m/z 506.0 [M + H]⁺. 2ax

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-p-tolyl-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.88;API-MS: m/z 450.2 [M + H]⁺. 2ay

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(3,4-dimethoxy-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.59; API-MS: m/z 496.2 [M + H]⁺. 2az

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(1-methyl-1H-indazol-5-yl)-1,4-dihydro-2H-isoquinolin- 3-one. HPLC:^(A)t_(Ret) = 2.53; API-MS: m/z 490.1 [M + H]⁺. 2ba

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-pyrrolidin-1-yl-phenyl)-1,4-dihydro-2H-isoquinolin- 3-one. HPLC:^(A)t_(Ret) = 2.73; LC-MS: m/z 506.1 [M + H]⁺. 2bb

1-(4-Bromo-phenyl)-7-((R)-sec-butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.10; LC-MS: m/z 523.4 [M + H]⁺. 2bc

7-((R)-sec-Butoxy)-1-(4-chloro-2-methyl-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.13; LC-MS: m/z 493.5 [M + H]⁺. 2bd

7-((R)-sec-Butoxy)-1-(4-chloro-3-fluoro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.11; LC-MS: m/z 497.6 [M + H]⁺. 2be

7-((R)-sec-Butoxy)-1-(4-chloro-3-methyl-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.17; LC-MS: m/z 493.4 [M + H]⁺. 2bf

7-((R)-sec-Butoxy)-1-(4-chloro-3-nitro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.08; LC-MS: m/z 524.5 [M + H]⁺. 2bg⁽¹⁾

1-(3-Amino-4-chloro-phenyl)-7-((R)-sec-butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.83; LC-MS: m/z 494.4 [M + H]⁺. 2bh

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-dimethylamino-2-methoxy-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.10; LC-MS: m/z 510.4[M + H]⁺. 2bi

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-dimethylamino-2-methyl-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.03; LC-MS: m/z 493.2[M + H]⁺. 2bj

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(2-methoxy-4-morpholin-4-yl-phenyl)-1,4-dihydro-2H- isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 2.50; LC-MS: m/z 551.2 [M + H]⁺. ⁽¹⁾The titlecompound (TFA salt, 21.1 mg, 0.29 mmol, 37%) was obtained as a colorlesssolid by reduction of the nitro group of Example 2bf (41.5 mg, 0.079mmol) analogously to Intermediate 3.3. Purification of the crudematerial was performed by reverse phase prep-HPLC (Waters system).

Example 3{2-[7-((R)-sec-Butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-5-chloro-phenyl}-urea

A mixture of Intermediate 3.3 (20 mg, 0.040 mmol) and NaOCN (7.9 mg,0.121 mmol) in AcOH (1 ml) and water (2 ml) was stirred at RT for 2 h.The reaction mixture was directly subjected to purification by reversephase prep-HPLC (Waters system) to yield the title compound (TFA salt,13.0 mg, 0.020 mmol, 49%) as a colorless solid. HPLC: ^(A)t_(Ret)=1.62min; LC-MS: m/z 537.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.78-0.92 (2t,J=7.5, 3H, mixture of diastereoisomers), 1.04-1.21 (2d, J=6.1, 3H,mixture of diastereoisomers), 1.41-1.67 (m, 2H, mixture ofdiastereoisomers), 2.88 (s, 6H), 3.64 (d, J=20.8, 1H), 3.73 (s, 3H),4.02 (dd, J=20.8, 4.6, 1H), 4.08-4.18 (m, 1H), 6.15 (br. s., 2H), 6.25(s, 1H), 6.65-6.73 (m, 2H), 6.79-6.85 (m, 2H), 6.86-6.93 (m, 2H),7.01-7.08 (m, 1H), 7.31 (dd, J=8.6, 2.2, 1H), 7.74 (dd, J=17.6, 2.2,1H), 7.99-8.05 (m, 1H).

Intermediate 3.1N-[1-(4-Chloro-2-nitro-phenyl)-meth-(E)-ylidene]N′,N′-dimethyl-benzene-1,4-diamine

The title compound (660 mg, 2.17 mmol, 59%) was obtained as a blacksolid from N,N-dimethyl-benzene-1,4-diamine (500 mg, 3.67 mmol) and4-chloro-2-nitro-benzaldehyde (681 mg, 3.67 mmol) analogously toIntermediate 1.4. ¹H NMR (400 MHz, DMSO-d₆): 2.96 (s, 6H), 6.74-6.80 (m,2H), 7.26-7.33 (m, 2H), 7.89 (dd, J=8.3, 2.0, 1H), 8.16-8.22 (m, 2H),8.82 (s, 1H).

Intermediate 3.2:7-((R)-sec-Butoxy)-1-(4-chloro-2-nitro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (322 mg, 0.61 mmol, 29%) was obtained as a brownishsolid from Intermediate 3.1 (650 mg, 2.14 mmol) and Intermediate 1.3(550 mg, 2.14 mmol) analogously to Example 1. Purification of the crudematerial was performed by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, heptane/TBME 95:5→100% TBME).TLC: R_(F)=0.19 (heptane/DCM/TBME 1:1:2); HPLC: ^(A)t_(Ret)=2.10 min;LC-MS: m/z 524.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.79-0.91 (2t,J=7.5, 3H, mixture of diastereoisomers), 1.06-1.20 (2d, J=6.1, 3H,mixture of diastereoisomers), 1.40-1.67 (m, 2H), 2.87 (s, 6H), 3.68 (d,J=20.8, 1 H), 3.77 (s, 3H), 4.02-4.17 (m, 2H), 6.42 (br. s., 1H),6.58-6.66 (m, 3H), 6.76-6.84 (m, 2H), 6.89 (s, 1H), 7.61-7.66 (m, 1H),7.71 (dd, J=8.6, 2.2, 1H), 7.91 (d, J=2.0, 1H).

Intermediate 3.3:1-(2-Amino-4-chloro-phenyl)-7-((R)-sec-butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

In a sealed reaction flask, a mixture of Intermediate 3.2 (322 mg, 0.61mmol) and Fe (343 mg, 6.1 mmol) in AcOH (1.8 ml), water (2.4 ml) andAcOEt (0.6 ml) was heated at 110° C. and stirred for 1 h. The suspensionwas cooled to RT, filtered through a Celite pad and the solid washedwith AcOEt. The filtrate was concentrated under vacuum, the resultingresidue was dissolved in AcOEt and washed with Na₂CO₃ 2M in water (2×).The organic phase was dried over Na₂SO₄, filtered and evaporated todryness. The resulting crude material was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,[heptane/DCM 1:1]/TBME containing 5% of 7M NH₃ in MeOH 95:5→4:6) toyield the title compound (253 mg, 0.51 mmol, 83%) as a brownish solid.TLC: R_(F)=0.31 (heptane/DCM/TBME containing 5% of 7M NH₃ in MeOH1:1:2); HPLC: ^(A)t_(Ret)=1.87 min; LC-MS: m/z 494.5 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆): 0.81-0.94 (m, 3H), 1.11-1.22 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.41-1.69 (m, 2H), 2.86 (s, 6H), 3.60 (d, J=20.5, 1H), 3.73 (s, 3H), 4.00 (d, J=20.3, 1H), 4.05-4.15 (m, 1H), 5.42-5.48 (m,2H), 6.17 (br. s., 1H), 6.46-6.51 (m, 1H), 6.54-6.57 (m, 1H), 6.58-6.64(m, 2H), 6.79 (s, 1H), 6.90-6.99 (m, 3H), 7.05 (dd, J=8.2, 1.8, 1 H).

Example 41-{2-[7-((R)-sec-Butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-5-chloro-phenyl}-3-methyl-urea

To a solution of Intermediate 3.3 (33 mg, 0.067 mmol) and pyridine(0.086 ml, 1.07 mmol) in MeCN (0.5 ml) was added methyl isocyanate(0.045 ml, 0.77 mmol) in portions over a period of 4 h at RT. Thereaction mixture was further stirred at RT for 14 h then directlysubjected to purification by reverse phase prep-HPLC (Waters system) toyield the title compound (TFA salt, 28.0 mg, 0.042 mmol, 63%) as acolorless solid. HPLC: ^(A)t_(Ret)=1.70 min; LC-MS: m/z 551.5 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆): 0.79-0.91 (2t, J=7.5, 3H, mixture ofdiastereoisomers), 1.04-1.19 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.41-1.66 (m, 2H), 2.60-2.66 (m, 3H), 2.88 (s, 6H),3.59-3.67 (m, J=20.8, 1H), 3.73 (s, 3H), 3.96-4.13 (m, 2H), 6.24 (s,1H), 6.28-6.36 (m, 1H), 6.64-6.72 (m, 2H), 6.79 (d, J=2.7, 1H), 6.83 (s,1H), 6.86-6.93 (m, 2H), 7.01-7.07 (m, 1H), 7.30 (dd, J=8.6, 3.9, 1H),7.69 (dd, J=19.3, 2.2, 1H), 7.96-8.03 (m, 1H).

Example 5N-{2-[7-((R)-sec-Butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-5-chloro-phenyl}-acetamide

To a mixture of Intermediate 3.3 (20 mg, 0.040 mmol) and pyridine (0.010ml, 0.12 mmol) in MeCN (0.5 ml) was added acetyl chloride (0.006 ml,0.081 mmol) at RT. The reaction mixture was stirred for 14 h thendirectly subjected to purification by reverse phase prep-HPLC (Waterssystem) to yield the title compound (TFA salt, 13.1 mg, 0.020 mmol, 50%)as a colorless solid. HPLC: ^(A)t_(Ret)=1.71 min; LC-MS: m/z 536.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.79-0.92 (2t, J=7.5, 3H, mixture ofdiastereoisomers), 1.04-1.19 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.42-1.65 (m, 2H), 1.90-1.99 (m, 3H), 2.90 (s, 6H),3.59-3.67 (m, 1H), 3.76 (d, J=1.5, 3H), 3.96-4.05 (m, 1H), 4.05-4.17 (m,1H), 6.34 (s, 1H), 6.67-6.76 (m, 2H), 6.78-6.89 (m, 4H), 7.15-7.26 (m,2H), 7.40-7.46 (m, 1H), 9.32 (d, J=17.1, 1H).

Example 67-((R)-sec-Butoxy)-1-(4-chloro-2-dimethylamino-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 3.3 (29 mg, 0.059 mmol) in DCM (1 ml) weresuccessively added AcOH (0.017 ml, 0.29 mmol), formaldehyde (37% inwater, 0.013 ml, 0.18 mmol) and NaBH(OAc)₃ (62.2 mg, 0.29 mmol) at RT.The reaction mixture was stirred for 4 h then Na₂CO₃ 2 M in water wasadded, the two phases were separated and the aqueous layer was furtherextracted with DCM (2×). The combined organic fractions were evaporatedto dryness and the resulting crude material was purified by reversephase prep-HPLC (Waters system) to yield the title compound (TFA salt,18 mg, 0.024 mmol, 41%) as a colorless solid. HPLC: ^(A)t_(Ret)=2.17min; LC-MS: m/z 522.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.79-0.91 (2t,J=7.5, 3H, mixture of diastereoisomers), 1.04-1.19 (2d, J=6.1, 3H,mixture of diastereoisomers), 1.42-1.66 (m, 2H), 2.29-2.37 (m, 6H), 2.85(s, 6H), 3.62 (d, J=20.8, 1H), 3.73 (s, 3H), 4.02-4.16 (m, 2H), 6.44(br. s., 1H), 6.62-6.71 (m, 2H), 6.78-6.91 (m, 4H), 7.11-7.16 (m, 1H),7.21-7.25 (m, 1H), 7.39 (d, J=8.3, 1H).

Example 72-[7-((R)-sec-Butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-5-chloro-benzamide

To a solution of Intermediate 7.4 (30 mg, 0.057 mmol) in DMF (0.3 ml)were successively added NH₄Cl (15.3 mg, 0.29 mmol), Et₃N (0.024 ml, 0.17mmol) and HATU (28.4 mg, 0.075 mmol). The reaction mixture was stirredat RT for 1 h then directly subjected to purification by reverse phaseprep-HPLC (Waters system) to yield the title compound (TFA salt, 19.3mg, 0.030 mmol, 53%) as a colorless solid. HPLC: ^(A)t_(Ret)=1.65 min;LC-MS: m/z 522.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.80-0.92 (2t,J=7.3, 3H, mixture of diastereoisomers), 1.08-1.21 (2d, J=6.1, 3H,mixture of diastereoisomers), 1.42-1.66 (m, 2H), 2.87 (s, 6H), 3.64 (d,J=20.5, 1 H), 3.73 (s, 3H), 4.05-4.16 (m, 2H), 6.61-6.68 (m, 2H),6.72-6.75 (m, 1H), 6.78-6.85 (m, 3H), 7.17 (s, 1H), 7.39-7.42 (m, 1H),7.44-7.49 (m, 1H), 7.50-7.54 (m, 1H), 7.55-7.61 (m, 1H), 7.77-7.84 (m,1H).

Intermediate 7.1: 5-Chloro-2-formyl-benzoic acid methyl ester

To a heterogeneous mixture of 5-chloro-2-formyl-benzoic acid (1.0 g,5.42 mmol) and K₂CO₃ (1.12 g, 8.13 mmol) in DMF (7 ml) was added MeI(0.41 ml, 6.5 mmol) at RT. The reaction mixture was stirred for 4 h thendiluted into Et₂O and washed with water (2×). The organic layer wasdried over Na₂SO₄, filtered and evaporated to dryness to yield the crudetitle compound (700 mg, 3.52 mmol, 65%) as a light yellow solid, whichwas used without further purification. HPLC: ^(A)t_(Ret)=1.84 min;LC-MS: m/z 199.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 3.91 (s, 3H),7.84-7.94 (m, 3H), 10.33 (s, 1H).

Intermediate 7.2:5-Chloro-2-{[(E)-4-dimethylamino-phenylimino]-methyl}-benzoic acidmethyl ester

The title compound (653 mg, 2.06 mmol, 50%) was obtained as a blacksolid from N,N-dimethyl-benzene-1,4-diamine (555 mg, 4.08 mmol) andIntermediate 7.1 (810 mg, 4.08 mmol) analogously to Intermediate 1.4. ¹HNMR (400 MHz, DMSO-d₆): 2.94 (s, 6H), 3.89 (s, 3H), 6.74-6.79 (m, 2H),7.23-7.29 (m, 2H), 7.74 (dd, J=8.4, 2.1, 1H), 7.84 (d, J=2.2, 1H), 8.15(d, J=8.6, 1H), 9.03 (s, 1H).

Intermediate 7.3:2-[7-((R)-sec-Butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-5-chloro-benzoicacid methyl ester

The title compound (537 mg, 1.0 mmol, 48%) was obtained as a brownishsolid from Intermediate 7.2 (653 mg, 2.06 mmol) and Intermediate 1.3(530 mg, 2.06 mmol) analogously to Example 1. Purification of the crudematerial was performed by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, [heptane/DCM 1:1]/TBME95:5→3:7). TLC: R_(F)=0.20 (heptane/DCM/TBME 1:1:2); HPLC:^(A)t_(Ret)=2.07 min; LC-MS: m/z 537.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.78-0.91 (2t, J=7.3, 3H, mixture of diastereoisomers),1.04-1.18 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.40-1.68 (m,2H), 2.85 (s, 6H), 3.67 (d, J=21.0, 1H), 3.73 (s, 3H), 3.76 (s, 3H),3.99-4.09 (m, 1H), 4.14 (d, J=21.0, 1H), 6.54-6.61 (m, 2H), 6.65-6.69(m, 1H), 6.71-6.77 (m, 2H), 6.80-6.84 (m, 1H), 6.86 (s, 1H), 7.51 (dd,J=8.6, 2.4, 1H), 7.55-7.62 (m, 2H).

Intermediate 7.4:2-[7-((R)-sec-Butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-5-chloro-benzoicacid

A mixture of Intermediate 7.3 (100 mg, 0.19 mmol) and LiOH monohydrate(39.1 mg, 0.93 mmol) in MeOH (1 ml) and water (0.5 ml) was heated at 50°C. and stirred for 3 h. The reaction mixture was cooled to RT,concentrated under vacuum, diluted into water and neutralized by theaddition of HCl 2 M in water (0.47 ml). The resulting slurry wasextracted with DCM (3×) and the combined organic fractions were driedover Na₂SO₄, filtered and evaporated to dryness to yield the crude titlecompound (87.5 mg, 0.17 mmol, 90%) as a brownish solid, which was usedin the next step without further purification. HPLC: ^(A)t_(Ret)=1.78min; LC-MS: m/z 523.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.78-0.91 (2t,J=7.3, 3H, mixture of diastereoisomers), 1.05-1.19 (2d, J=6.1, 3H,mixture of diastereoisomers), 1.38-1.65 (m, 2H), 2.86 (s, 6H), 3.63-3.70(m, J=20.8, 1H), 3.75 (s, 3H), 3.99-4.09 (m, 1H), 4.15 (d, J=21.0, 1H),6.60-6.67 (m, 2H), 6.76-6.82 (m, 2H), 6.84 (s, 1H), 6.88 (d, J=2.9, 1H),7.03-7.07 (m, 1H), 7.55-7.58 (m, 2H), 7.65-7.68 (m, 1H), 13.60 (br. s.,1H).

Example 87-((R)-sec-Butoxy)-1-(4-chloro-2-hydroxymethyl-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 7.3 (150 mg, 0.28 mmol) in THF (3 ml) weresuccessively added LiBH₄ (18.3 mg, 0.84 mmol) and MeOH (0.034 ml, 0.84mmol) at RT. The reaction mixture was stirred at RT for 3 h thenquenched cautiously by the addition of HCl 2 M in water, diluted intoDCM and washed with Na₂CO₃ 2 M in water. The aqueous layer was furtherextracted with DCM (2×) and the combined organic fractions were driedover Na₂SO₄, filtered and evaporated to dryness. The resulting crudematerial was purified by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, [heptane/DCM 1:1]/TBMEcontaining 5% of 7 M NH₃ in MeOH 95:5→3:7) to yield the title compound(95.2 mg, 0.19 mmol, 67%) as an off-white solid. TLC: R_(F)=0.18(heptane/DCM/TBME containing 1% of 7 M NH₃ in MeOH 1:1:2); HPLC:^(A)t_(Ret)=1.73 min; LC-MS: m/z 509.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.76-0.88 (2t, J=7.5, 3H, mixture of diastereoisomers),1.02-1.14 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.37-1.65 (m,2H), 2.85 (s, 6H), 3.67 (d, J=21.3, 1H), 3.76 (s, 3H), 3.99-4.27 (m,4H), 5.46 (br. s., 1H), 6.22 (br. s., 1H), 6.54-6.61 (m, 2H), 6.69-6.75(m, 2H), 6.78 (s, 1H), 6.83 (s, 1H), 7.26 (s, 3H).

Example 91-(2-Aminomethyl-4-chloro-phenyl)-7-((R)-sec-butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

In a sealed reaction flask, a mixture of Example 8 (20 mg, 0.039 mmol)and SOCl₂ (0.014 ml, 0.20 mmol) in DCM (0.4 ml) was heated at 40° C. andstirred for 1 h. The reaction mixture was cooled to RT and evaporated todryness. To the residue was added a 7 M solution of NH₃ in MeOH (1.0 ml,7.03 mmol) and the resulting solution was heated at 70° C. and stirredfor 14 h. The reaction mixture was cooled to RT and directly subjectedto purification by reverse phase prep-HPLC (Waters system) to yield thetitle compound (TFA salt, 6.8 mg, 0.009 mmol, 23%) as a colorless solid.HPLC: ^(A)t_(Ret)=1.38 min; LC-MS: m/z 508.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.78-0.90 (2t, J=7.5, 3H, mixture of diastereoisomers),1.03-1.16 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.41-1.62 (m,2H), 2.88 (s, 6H), 3.70 (d, J=21.0, 1H), 3.79 (s, 3H), 3.88-3.98 (m,2H), 4.05 (d, J=20.8, 1H), 4.09-4.21 (m, 1H), 6.20 (br. s., 1H),6.55-6.59 (m, 1H), 6.60-6.65 (m, 2H), 6.70-6.76 (m, 2H), 6.91 (s, 1H),7.19 (d, J=8.3, 1H), 7.35-7.41 (m, 2H), 8.13 (br. s., 2H).

Example 10N-{2-[7-((R)-sec-Butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-5-chloro-benzyl}-acetamide

To a mixture of crude Example 9 (24 mg, 0.047 mmol) and Et₃N (0.020 ml,0.14 mmol) in DCM (0.4 ml) was added acetyl chloride (0.007 ml, 0.094mmol) at RT. The reaction mixture was stirred for 30 min and evaporatedto dryness. The resulting crude material was purified by reverse phaseprep-HPLC (Waters system) to yield the title compound (TFA salt, 12 mg,0.018 mmol, 38%) as a colorless solid. HPLC: ^(A)t_(Ret)=1.70 min;LC-MS: m/z 550.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.76-0.89 (2t,J=7.5, 3H, mixture of diastereoisomers), 1.00-1.16 (2d, J=6.1, 3H,mixture of diastereoisomers), 1.38-1.62 (m, 2H), 1.82 (s, 3H), 2.87 (s,6H), 3.68 (d, J=21.3, 1H), 3.77 (s, 3H), 4.04-4.18 (m, 2H), 4.19-4.29(m, 1H), 6.29 (br. s., 1H), 6.57-6.65 (m, 3H), 6.70-6.76 (m, 2H), 6.85(s, 1H), 7.13-7.20 (m, 2H), 7.22-7.27 (m, 1H), 8.28-8.35 (m, 1H).

Example 11

Compounds 11a to 11f were obtained by reaction of Intermediate 3.3 (oranalogues prepared similarly) with various isocyanates, acyl chloridesor aldehydes analogously to Example 4, 5 and 6 respectively, or byreaction of Intermediate 7.4 (or analogues prepared similarly) withvarious amines analogously to Example 7, or by reaction of Example 8 (oranalogues prepared similarly) with various amines analogously to Example9.

# Structure Name/HPLC/MS 11a

N-{5-Chloro-2-[6,7-diethoxy-2-(4-methoxy-phenyl)-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenyl}- acetamide. HPLC:^(A)t_(Ret) = 2.08; API-MS: m/z 509.2 [M + H]⁺. 11b

1-{2-[7-((R)-sec-Butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-5-chloro-phenyl}-3-ethyl-urea. HPLC: ^(A)t_(Ret) = 1.80; LC-MS: m/z565.5 [M + H]⁺. 11c

N-{2-[7-((R)-sec-Butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-5-chloro-phenyl}-propionamide. HPLC: ^(A)t_(Ret) =1.82; LC-MS: m/z 550.3 [M + H]⁺. 11d

7-((R)-sec-Butoxy)-1-[4-chloro-2-(ethyl-methyl-amino)-phenyl]-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.29;LC-MS: m/z 536.6 [M + H]⁺. 11e

2-[7-((R)-sec-Butoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-3-oxo-1,2,3,4-tetrahydro-isoquinolin-1-yl]-5-chloro-N-methyl-benzamide. HPLC: ^(A)t_(Ret) = 1.75; LC-MS: m/z 536.4[M + H]⁺. 11f

7-((R)-sec-Butoxy)-1-(4-chloro-2-methylaminomethyl-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.40; LC-MS: m/z 522.3[M + H]⁺

Example 121-(4-Chloro-phenyl)-6,7-diethoxy-2-[4-methyl-2-(3-morpholin-4-yl-propoxy)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one.(Methode A)

To a solution of Intermediate 12.3 (25 mg, 0.055 mmol) in DCM (1.5 ml)were successively added 3-morpholin-4-yl-propan-1-ol (0.009 ml, 0.066mmol), supported PPh₃ (loading of 1.52 mmol/g, 109 mg, 0.166 mmol) andDTAD (19.1 mg, 0.083 mmol). The reaction mixture was shaken at RT for 3h, then filtered and the resin was washed with DCM. The filtrate wasevaporated to dryness and the resulting residue was purified by reversephase prep-HPLC (Waters system) to yield the title compound (TFA salt,9.9 mg, 0.014 mmol, 26%). HPLC: ^(A)t_(Ret)=1.98 min; API-MS: m/z 580.6[M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 1.27-1.52 (m, 6H), 1.97-2.15 (m, 2H),2.36 (s, 3H), 2.50-2.82 (m, 1H), 2.83-3.28 (m, 4H), 3.38-4.25 (m, 13H),5.66 (s, 1H), 6.54-6.80 (m, 2H), 6.82-7.07 (m, 3H), 7.15-7.40 (m, 4H).

Intermediate 12.1:2-(tert-Butyl-dimethyl-silanyloxy)-4-methyl-phenylamine

To a solution of 2-amino-5-methyl-phenol (500 mg, 4.0 mmol) andimidazole (298 mg, 4.4 mmol) in DMF (5 ml) was added TBDMSCl (660 mg,4.4 mmol). The reaction mixture was stirred at RT for 3 h then dilutedinto water and extracted with AcOEt. The organic fraction was dried overNa₂SO₄, filtered and evaporated to dryness. The resulting residue waspurified by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, heptane/TBME containing 5% of 7M NH₃ in MeOH95:5→8:2) to yield the title compound (724 mg, 3.1 mmol, 77%) as aredish oil. TLC: R_(F)=0.94 (heptane/DCM/TBME 1:1:2 containing 5% of 7MNH₃ in MeOH); HPLC: ^(A)t_(Ret)=1.80 min; API-MS: m/z 238.1 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃): 0.26 (s, 6H), 1.04 (s, 9H), 2.23 (s, 3H), 3.56(br. s., 1H), 6.56-6.67 (m, 3H).

Intermediate 12.2:[2-(tert-Butyl-dimethyl-silanyloxy)-4-methyl-phenyl]-[1-(4-chloro-phenyl)-meth-(E)-ylidene]-amine

The title intermediate (1.06 g, 2.94 mmol, 97%) was obtained as abrownish solid from Intermediate 12.1 (724 mg, 3.05 mmol) and4-chloro-benzaldehyde (429 mg, 3.05 mmol) analogously to Intermediate1.4. ¹H NMR (400 MHz, CDCl₃): 0.17 (s, 6H), 0.99 (s, 9H), 2.33 (s, 3H),6.73-6.83 (m, 2H), 6.94 (d, J=7.8, 1H), 7.42-7.48 (m, 2H), 7.81-7.87 (m,2H), 8.43 (s, 1H).

Intermediate 12.3: (3,4-Diethoxy-phenyl)-acetyl chloride

To a solution of (3,4-diethoxy-phenyl)-acetic acid (2.0 g, 8.9 mmol) inDCM (6 ml) were successively added oxalylchloride (1.13 ml, 13.4 mmol)and a catalytic amount of DMF (0.069 ml, 0.89 mmol) at 0° C. (ice bath).The reaction mixture was stirred at 0° C. for 1 h then evaporated todryness under vacuum to yield the crude (3,4-diethoxy-phenyl)-acetylchloride (2.2 g, 8.9 mmol, quant.) as a brownish oil which was used inthe next step without further purification.

Intermediate 12.4:1-(4-Chloro-phenyl)-6,7-diethoxy-2-(2-hydroxy-4-methyl-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (600 mg, 1.33 mmol, 45%) was obtained as a yellowfoam from Intermediate 12.2 (1.06 g, 2.94 mmol) and Intermediate 12.3(715 mg, 2.94 mmol) analogously to Example 1. Longer reaction time (14h) was required after the addition of methanesulfonic acid to cleave thesilyl group in-situ. The title compound was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,[heptane/DCM 1:1]/TBME 95:5→4:6). TLC: R_(F)=0.33 (heptane/DCM/TBME1:1:2); HPLC: ^(A)t_(Ret)=2.51 min; API-MS: m/z 452.2 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃): 1.44-1.52 (m, 6H), 2.33 (s, 3H), 3.73 (s, 2H),4.04-4.17 (m, 4H), 5.95 (s, 1H), 6.73-6.82 (m, 4H), 6.87-6.91 (m, 1H),7.00-7.07 (m, 3H), 7.21-7.26 (m, 2H).

Example 13{2-[1-(4-Chloro-phenyl)-6,7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-5-methyl-phenoxy}-aceticacid

A mixture of Intermediate 13.1 (44 mg, 0.084 mmol) in MeOH (0.8 ml) andwater (0.2 ml) was treated with LiOH monohydrate (10.6 mg, 0.25 mmol) atRT and stirred for 1 h. The reaction mixture was neutralized by theaddition of HCl 0.5 M in water then extracted with DCM. The organicfraction was dried over Na₂SO₄, filtered and evaporated to dryness. Theresulting residue was purified by reverse phase prep-HPLC (Waterssystem) to yield the title compound (8.5 mg, 0.017 mmol, 20% for 2steps). HPLC: ^(A)t_(Ret)=2.41 min; LC-MS: m/z 510.8 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆): 1.26 (t, J=6.9, 3H), 1.33 (t, J=6.9, 3H), 2.26 (s, 3H),3.53 (d, J=19.6, 1H), 3.89 (d, J=19.5, 1H), 3.90-4.01 (m, 2H), 4.05 (q,J=6.9 Hz, 2H), 4.44 (d, J=15.9, H), 4.59 (d, J=15.9, 1H), 5.98 (s, 1H),6.64-6.69 (m, 1H), 6.72 (s, 1H), 6.77 (d, J=7.8, 1H), 6.81 (s, 2H), 7.23(d, J=2.1, 4H).

Intermediate 13.1:{2-[1-(4-Chloro-phenyl)-6,7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-5-methyl-phenoxy}-aceticacid methyl ester. (Methode B)

To a solution of Intermediate 12.4 (38 mg, 0.084 mmol) in DMF (0.5 ml)were successively added Cs₂CO₃ (54.8 mg, 0.17 mmol) and bromo-aceticacid methyl ester (0.012 ml, 0.13 mmol). The reaction mixture wasstirred at RT for 30 min then partitioned between water and AcOEt. Theorganic phase was separated, dried over Na₂SO₄, filtered and evaporatedto dryness to yield the crude title intermediate (44.1 mg) as a yellowoil, which was used in the next step without further purification. HPLC:^(A)t_(Ret)=2.66 min; LC-MS: m/z 525.9 [M+H]⁺.

Example 141-(4-Chloro-phenyl)-6,7-diethoxy-2-[4-methyl-2-(2H-tetrazol-5-ylmethoxy)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 12.4 (50 mg, 0.11 mmol) in acetone (1 ml)were successively added K₂CO₃ (45.4 mg, 0.33 mmol) andbromo-acetonitrile (0.011 ml, 0.17 mmol). The reaction mixture wasstirred at RT for 3 h then diluted into AcOEt and washed with water. Theorganic phase was dried over Na₂SO₄, filtered and evaporated to dryness.The resulting residue was dissolved in DMF (0.5 ml) then NH₄Cl (19.6 mg,0.33 mmol) and NaN₃ (21.4 mg, 0.033 mmol) were added and theheterogeneous mixture was heated at 100° C. and stirred for 24 h. Thereaction mixture was cooled to RT, filtered and directly subjected topurification by reverse phase prep-HPLC (Waters system) to yield thetitle compound (25 mg, 0.047 mmol, 43%). HPLC: ^(A)t_(Ret)=2.47 min;LC-MS: m/z 535.8 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 1.35 (t, J=7.0, 3H),1.43 (t, J=7.0, 3H), 2.34 (s, 3H), 3.60-3.78 (m, 1H), 3.83-4.20 (m, 5H),5.16-6.05 (m, 3H), 6.55-7.38 (m, 9H).

Example 15

Compounds 15a to 15l were obtained by reaction of Intermediate 12.4 (oranalogues prepared similarly) with various aliphatic alcohols orhalogenides analogously to Example 12 (Methode A) or Intermediate 13.1(Methode 8) respectively.

# Structure Name/HPLC/MS 15a

1-(4-Chloro-phenyl)-6,7-diethoxy-2-[4-methyl-2-(2-morpholin-4-yl-ethoxy)-phenyl]-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.95; LC-MS: m/z 566.9 [M + H]⁺. 15b

1-(4-Chloro-phenyl)-2-[2-(3-dimethylamino-propoxy)-4-methyl-phenyl]-6,7-diethoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.97; LC-MS: m/z 537.9 [M + H]⁺. 15c

1-(4-Chloro-phenyl)-6,7-diethoxy-2-{4-methyl-2-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.77; API-MS: m/z 579.7 [M + H]⁺.15d

1-(4-Chloro-phenyl)-6,7-diethoxy-2-{4-methyl-2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.77; API-MS: m/z 592.4 [M +H]⁺. 15e

{4-Chloro-2-[1-(4-chloro-phenyl)-6,7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-phenoxy}-acetic acid methyl ester.HPLC: ^(A)t_(Ret) = 2.76; LC-MS: m/z 545.8 [M + H]⁺. 15f

{4-Chloro-2-[1-(4-chloro-phenyl)-6,7-diethoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenoxy}-acetic acid. HPLC: ^(A)t_(Ret)= 2.49; LC-MS: m/z 531.8 [M + H]⁺. 15g

2-[5-Chloro-2-(2-dimethylamino-ethoxy)-phenyl]-1-(4-chloro-phenyl)-6,7-diethoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.00; API-MS: m/z 544.7 [M + H]⁺. 15h

2-[5-Chloro-2-(3-morpholin-4-yl-propoxy)-phenyl]-1-(4-chloro-phenyl)-6,7-diethoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.03; LC-MS: m/z 601.8 [M + H]⁺. 15i

2-[5-Chloro-2-(2-morpholin-4-yl-ethoxy)-phenyl]-1-(4-chloro-phenyl)-6,7-diethoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.03; LC-MS: m/z 586.8 [M + H]⁺. 15j

2-[5-Chloro-2-(3-dimethylamino-propoxy)-phenyl]-1-(4-chloro-phenyl)-6,7-diethoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.03; LC-MS: m/z 558.9 [M + H]⁺. 15k

2-[5-Chloro-2-(3-hydroxy-propoxy)-phenyl]-1-(4-chloro-phenyl)-6,7-diethoxy-1,4-dihydro-1H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.57; LC-MS: m/z 531.7 [M + H]⁺. 15l⁽¹⁾

2-[5-Chloro-2-(2-hydroxy-ethoxy)-phenyl]-1-(4-chloro-phenyl)-6,7-diethoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret)= 2.55; LC-MS: m/z 517.8 [M + H]⁺. ⁽¹⁾The title compound (2.5 mg, 0.005mmol, 15%) was obtained by reduction of the methyl ester function ofExample 15e (17.4 mg, 0.032 mmol) analogously to Example 8. Purificationof the crude material was performed by reverse phase prep-HPLC (Waterssystem).

Example 166-((R)-sec-Butoxy)-4-(4-chloro-phenyl)-3-(4-dimethylamino-phenyl)-7-methoxy-3,4-dihydro-1H-quinazolin-2-one.(Methode A)

To a mixture of Intermediate 16.7 (90 mg, 0.19 mmol) and ammoniumformate (237 mg, 3.77 mmol) in MeOH (2 ml) was added Pd/C (2 mg, 0.019mmol). The reaction mixture was heated at 60° C., stirred for 14 h, thencooled to RT and filtered through a Celite pad. The filter cake waswashed with MeOH and the filtrate was concentrated under vacuum. Theresulting residue was dissolved in AcOEt and washed successively withwater and Na₂CO₃ 2M. The organic phase was dried over Na₂SO₄, filteredand evaporated to dryness. The resulting residue was purified byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, [heptane/DCM 1:1]/TBME 95:5→100% TBME) to yield the titlecompound (49 mg, 0.10 mmol, 54%) as an off-white solid. TLC: R_(F)=0.14(heptane/DCM/TBME 1:1:2); HPLC: ^(A)t_(Ret)=1.98 min; LC-MS: m/z 480.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.81-0.93 (m, 3H, mixture ofdiastereoisomers), 1.06-1.16 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.40-1.64 (m, 2H), 2.85 (s, 6H), 3.70 (s, 3H),3.99-4.13 (m, 1H), 5.83 (s, 1H), 6.51-6.54 (m, 1H), 6.59-6.64 (m, 2H),6.77-6.80 (m, 1H), 6.88-6.94 (m, 2H), 7.27-7.39 (m, 4H), 9.36 (s, 1H).

Intermediate 16.1: 3-((R)-sec-Butoxy)-4-methoxy-benzaldehyde

To a solution of 3-hydroxy-4-methoxy-benzaldehyde (4 g, 26.3 mmol), PPh₃(9.65 g, 36.8 mmol) and (S)-butan-2-ol (2.9 ml, 31.5 mmol) in DCM (100ml) was slowly added DTAD (9.08 g, 39.4 mmol) at 0° C. (ice bath). Afterthe addition, the yellow solution was allowed to warm to RT and furtherstirred for 30 min. The reaction mixture was washed successively withHCl 2M in water (2×) and Na₂CO₃ 2M. The organic phase was dried overNa₂SO₄, filtered and evaporated to dryness. The resulting crude materialwas purified by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, heptane/TBME 95:5→7:3) to yield the titlecompound (2.42 g, 11.6 mmol, 44%) as a light yellow oil. TLC: R_(F)=0.4(heptane/TBME 1:1); HPLC: ^(A)t_(Ret)=1.93 min; LC-MS: m/z 209.2 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆): 0.93 (t, J=7.5, 3H), 1.24 (d, J=6.1, 3H),1.53-1.75 (m, 2H), 3.87 (s, 3H), 4.38-4.47 (m, 1H), 7.18 (d, J=8.3, 1H),7.39 (d, J=1.7, 1H), 7.54 (dd, J=8.3, 2.0, 1H), 9.83 (s, 1H).

Intermediate 16.2:[3-((R)-sec-Butoxy)-4-methoxy-phenyl]-(4-chloro-phenyl)-methanol

A solution of Intermediate 16.1 (576 mg, 2.77 mmol) in THF (20 ml) wascooled to 0° C. (ice bath) and treated with 4-chlorophenylmagnesiumbromide (1M THF solution, 4.15 ml, 4.15 mmol). After the addition, thereaction mixture was further stirred for 1.5 h at 0° C. then quenched bythe addition of a saturated aqueous NH₄Cl solution (20 ml). Theresulting slurry was diluted into water and extracted with DCM (2×). Thecombined organic fractions were dried over Na₂SO₄, filtered andevaporated to dryness to yield the crude title compound (1.01 g) as ayellow oil, which was used in the next step without furtherpurification. HPLC: ^(A)t_(Ret)=2.51 min; API-MS: m/z 319.2 [M−H]⁺; ¹HNMR (400 MHz, DMSO-d₆): 0.86-0.93 (m, 3H, mixture of diastereoisomers),1.13-1.21 (m, 3H, mixture of diastereoisomers), 1.47-1.70 (m, 2H), 3.71(s, 3H), 4.19-4.28 (m, 1H), 5.62 (d, J=3.9, 1H), 5.86 (d, J=4.2, 1H),6.81-6.90 (m, 2H), 6.93 (d, J=1.7, 1H), 7.33-7.38 (m, 4H).

Intermediate 16.3:[3-((R)-sec-Butoxy)-4-methoxy-phenyl]-(4-chloro-phenyl)-methanone

To a solution of Intermediate 16.2 (1.01 g) in CHCl₃ (15 ml) was addedMnO₂ (2.88 g, 33.1 mmol) in one portion. The suspension was refluxed for3 h, then cooled to RT and filtered through a Celite pad. The filtercake was washed with DCM and the filtrate was evaporated to dryness toyield the crude title compound (965 mg) as an orange oil, which was usedin the next step without further purification. HPLC: ^(A)t_(Ret)=2.85min; LC-MS: m/z 319.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.92 (t, J=7.3,3H), 1.24 (d, J=6.1, 3H), 1.53-1.74 (m, 2H), 3.87 (s, 3H), 4.33-4.42 (m,1H), 7.11 (d, J=8.3, 1H), 7.28-7.36 (m, 2H), 7.60-7.65 (m, 2H),7.69-7.75 (m, 2H).

Intermediate 16.4:[5-((R)-sec-Butoxy)-4-methoxy-2-nitro-phenyl]-(4-chloro-phenyl)-methanone

To a solution of Intermediate 16.3 (965 mg) in AcOH (10 ml) was slowlyadded HNO₃ (0.86 ml, 19.3 mmol) at 0° C. (ice bath). After the addition,the reaction mixture was allowed to warm to RT, then further stirred for1 h and poured into cold water. The resulting precipitate was collectedby filtration and washed with 2M aqueous NaHCO₃ solution. The solid wasdissolved in DCM, dried over Na₂SO₄, filtered and evaporated to drynessto yield the title compound (1.0 g, 2.76 mmol) as a brownish solid,which was used in the next step without further purification. HPLC:^(A)t_(Ret)=2.82 min; LC-MS: m/z 364.0 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.89 (t, J=7.3, 3H), 1.23 (d, J=5.9, 3H), 1.54-1.76 (m, 2H),3.96 (s, 3H), 4.61-4.71 (m, 1H), 7.26 (s, 1H), 7.57-7.63 (m, 2H),7.69-7.75 (m, 2H), 7.79 (s, 1H).

Intermediate 16.5:5-((R)-sec-Butoxy)-3-(4-chloro-phenyl)-6-methoxy-benzo[c]isoxazole

In a sealed reaction flask, a mixture of Intermediate 16.4 (1.0 g, 2.76mmol) and SnCl₂ (5.24 g, 27.6 mmol) in EtOH (10 ml) was heated at 80° C.and stirred for 1 h. The resulting suspension was cooled to RT andfiltered. The solid was dissolved in DCM (200 ml) and washed with a 1Maqueous NaOH solution (2×). The organic layer was dried over Na₂SO₄,filtered and evaporated to dryness to yield the title compound (581 mg,1.75 mmol, 63%) as a yellow solid, which was used in the next stepwithout further purification. HPLC: ^(A)t_(Ret)=2.97 min; LC-MS: m/z332.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.95 (t, J=7.5, 3H), 1.29 (d,J=6.1, 3H), 1.58-1.79 (m, 2H), 3.89 (s, 3H), 4.60-4.71 (m, 1H), 6.94 (s,1H), 7.12 (s, 1H), 7.62-7.69 (m, 2H), 8.01-8.08 (m, 2H).

Intermediate 16.6:[2-Amino-5-((R)-sec-butoxy)-4-methoxy-phenyl]-(4-chloro-phenyl)-methanone

In a sealed reaction flask, a mixture of Intermediate 16.5 (522 mg, 1.57mmol) and Fe (879 mg, 15.7 mmol) in AcOH (3 ml), water (4 ml) and AcOEt(1 ml) was heated at 110° C. and stirred for 30 min. The resultingsuspension was cooled to RT, neutralized by the addition of a saturatedaqueous NaHCO₃ solution to pH 7 and filtered through a Celite pad. Thesolid was washed with AcOEt and the biphasic filtrate was transferredinto a separating funnel. The aqueous layer was separated and furtherextracted with AcOEt (3 x). The combined organic fractions were driedover Na₂SO₄, filtered and evaporated to dryness. The resulting crudematerial was purified by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; isocratic elution, [heptane/DCM 1:1]/TBME 95:5) toyield the title compound (525 mg, 1.57 mmol, quant.) as a brownishsolid. TLC: R_(F)=0.57 (heptane/DCM/TBME 1:1:2); HPLC: ^(A)t_(Ret)=2.64min; LC-MS: m/z 334.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.82 (t, J=7.5,3H), 1.07 (d, J=6.1, 3H), 1.36-1.60 (m, 2H), 3.79 (s, 3H), 3.80-3.88 (m,1H), 6.43 (s, 1H), 6.68 (s, 1H), 7.20 (s, 2H), 7.49-7.59 (m, 4H).

Intermediate 16.7:6-((R)-sec-Butoxy)-4-(4-chloro-phenyl)-3-(4-dimethylamino-phenyl)-7-methoxy-3H-quinazolin-2-one

To a solution of Intermediate 16.6 (300 mg, 0.9 mmol) in toluene (8 ml)was added (4-isocyanato-phenyl)-dimethyl-amine (219 mg, 1.35 mmol). Thereaction mixture was heated at 110° C. and stirred for 4.5 days. PTSA(15.48 mg, 0.09 mmol) was then added and the mixture was further stirredat 110° C. for additional 14 h. The reaction mixture was cooled to RTand evaporated to dryness. The resulting residue was purified byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, DCM/MeOH 99:1→9:1) to yield the title compound (100 mg, 0.21mmol, 23%) as a dark solid. TLC: R_(F)=0.29 (DCM/MeOH 9:1); HPLC:^(A)t_(Ret)=2.07 min; LC-MS: m/z 478.0 [M+H]⁺.

Example 174-(4-Chloro-phenyl)-6,7-dimethoxy-3-(4-methoxy-phenyl)-3,4-dihydro-1H-quinazolin-2-one.(Methode B)

To a solution of the crude Intermediate 17.1 (25 mg) in MeOH (1 ml) wasadded NaBH₄ (4.7 mg, 0.12 mmol) in one portion at RT. The reactionmixture was stirred for 3 h and concentrated under vacuum. The residuewas dissolved in DCM, washed with water and the organic phase was driedover Na₂SO₄, filtered and evaporated to dryness. The resulting crudematerial was purified by reverse phase prep-HPLC (Waters system) toyield the title compound (9.5 mg, 0.022 mmol, 38%). HPLC:^(A)t_(Ret)=2.17 min; API-MS: m/z 425.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):3.70 (s, 3H), 3.78 (s, 3H), 3.85 (s, 3H), 5.81 (s, 1H), 6.60 (s, 1H),6.62 (s, 1H), 6.83-6.89 (m, 2H), 6.95-7.01 (m, 2H), 7.17-7.23 (m, 2H),7.26-7.32 (m, 2H).

Intermediate 17.1:4-(4-Chloro-phenyl)-6,7-dimethoxy-3-(4-methoxy-phenyl)-3H-quinazolin-2-one

The crude title intermediate (136 mg) was obtained as a light yellowsolid from (2-amino-4,5-dimethoxy-phenyl)-(4-chloro-phenyl)-methanone(100 mg, 0.34 mmol, purchased by ChemCollect GmbH) and1-isocyanato-4-methoxy-benzene (0.044 ml, 0.34 mmol) analogously toIntermediate 16.7. The crude intermediate was used in the next stepwithout further purification. HPLC: ^(A)t_(Ret)=2.53 min; API-MS: m/z441.1 [M+H]⁺.

Example 186-((R)-sec-Butoxy)-4-(4-chloro-phenyl)-3-(4-dimethylamino-phenyl)-7-methoxy-1-methyl-3,4-dihydro-1H-quinazolin-2-one

To a solution of Example 16 (20 mg, 0.042 mmol) in THF (0.3 ml) wascautiously added NaH (60% in mineral oil, 3.3 mg, 0.083 mmol) at RT. Themixture was heated at 50° C. and stirred for 30 min. MeI (0.005 ml,0.083 mmol) was added at 50° C. and the reaction mixture was furtherstirred for 1 h then cooled to RT and quenched by the addition of MeOH.The resulting clear solution was directly subjected to purification byreverse phase prep-HPLC (Waters system) to yield the title compound (TFAsalt, 9.4 mg, 0.015 mmol, 37%) as an off-white solid. HPLC:^(A)t_(Ret)=2.10 min; LC-MS: m/z 494.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.84-0.94 (m, 3H, mixture of diastereoisomers), 1.09-1.19 (m,3H, mixture of diastereoisomers), 1.43-1.66 (m, 2H), 2.88 (s, 6H), 3.30(s, 3H), 3.80 (s, 3H), 4.08-4.21 (m, 1H), 5.83 (s, 1H), 6.63 (s, 1H),6.67-6.78 (m, 2H), 6.91-7.02 (m, 3H), 7.25-7.32 (m, 2H), 7.34-7.41 (m,2H).

Example 19

Compounds 19a to 19f were obtained by reaction of Intermediate 16.6 (oranalogues prepared similarly) or the commercially available(2-amino-4,5-dimethoxy-phenyl)-(4-chloro-phenyl)-methanone with variousisocyanates analogously to Example 16 (Methode A) or Example 17 (MethodeB), or by alkylation of Example 16 (or analogues prepared similarly)with various alkyl halogenides as described for Example 18.

# Structure Name/HPLC/MS/NMR 19a

4-(4-Chloro-phenyl)-3-(4-dimethylamino-phenyl)-6,7-dimethoxy-3,4-dihydro-1H-quinazolin-2-one. HPLC: ^(A)t_(Ret) =1.54;LC-MS: m/z 438.1 [M + H]⁺. 19b

6-((R)-sec-Butoxy)-4-(4-chloro-phenyl)-7-methoxy-3-(4-methoxy-phenyl)-3,4-dihydro-1H-quinazolin-2-one. HPLC: ^(A)t_(Ret) =2.65; LC-MS: m/z 467.1 [M + H]⁺. 19c

4-(4-Chloro-phenyl)-3-(4-dimethylamino-phenyl)-6,7-dimethoxy-1-methyl-3,4-dihydro-1H-quinazolin-2-one. HPLC: ^(A)t_(Ret) =1.69; LC-MS: m/z 452.0 [M + H]⁺. 19d

4-(4-Chloro-phenyl)-3-(4-dimethylamino-phenyl)-1-ethyl-6,7-dimethoxy-3,4-dihydro-1H-quinazolin-2-one. HPLC: ^(A)t_(Ret) =1.79: LC-MS: m/z 466.1 [M + H]⁺. 19e

4-(4-Chloro-phenyl)-3-(4-dimethylamino-phenyl)-1-isopropyl-6,7-dimethoxy-3,4-dihydro-1H-quinazolin-2- one. HPLC:^(A)t_(Ret) = 1.94; LC-MS: m/z 480.1 [M + H]⁺. 19f

6-((R)-sec-Butoxy)-4-(4-chloro-phenyl)-3-(4-dimethylamino-phenyl)-1-ethyl-7-methoxy-3,4-dihydro-1H-quinazolin-2-one. HPLC: ^(A)t_(Ret) = 2.17; LC-MS: m/z 508.6 [M +H]⁺.

Example 201-(4-Chloro-phenyl)-7-methoxy-2-(4-methoxy-phenyl)-6-(2-morpholin-4-yl-ethoxy)-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 20.3 (15 mg, 0.037 mmol) in DCM (0.5 ml)were successively added 2-morpholin-4-yl-ethanol (0.005 ml, 0.044 mmol),supported PPh₃ (loading of 1.52 mmol/g, 72.2 mg, 0.11 mmol) and DTAD(12.6 mg, 0.055 mmol). The reaction mixture was shaken at RT for 3 h,then filtered and the resin was washed with DCM. The filtrate wasevaporated to dryness and the resulting residue was purified by reversephase prep-HPLC (Waters system) to yield the title compound (TFA salt, 5mg, 0.008 mmol, 21%). HPLC: ^(A)t_(Ret)=1.66 min; API-MS: m/z 523.2[M+H]⁺.

Intermediate 20.1:[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-(4-methoxy-phenyl)-amine

The title intermediate (1.88 g, 7.65 mmol, 94%) was obtained as acolorless solid from 4-methoxy-phenylamine (1 g, 8.12 mmol) and4-chloro-benzaldehyde (1.14 g, 8.12 mmol) analogously to Intermediate1.4. ¹H NMR (400 MHz, CDCl₃): 3.86 (s, 3H), 6.93-6.98 (m, 2H), 7.24-7.28(m, 2H), 7.43-7.48 (m, 2H), 7.83-7.87 (m, 2H), 8.47 (s, 1H).

Intermediate 20.2: (3-Benzyloxy-4-methoxy-phenyl)-acetyl chloride

The title intermediate (534 mg, 1.84 mmol, quant.) was obtained as ayellow solid from (3-benzyloxy-4-methoxy-phenyl)-acetic acid (500 mg,1.84 mmol) analogously to Intermediate 1.3.

Intermediate 20.3:1-(4-Chloro-phenyl)-6-hydroxy-7-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (340 mg, 0.83 mmol, 45%) was obtained fromIntermediate 20.1 (452 mg, 1.84 mmol) and Intermediate 20.2 (535 mg,1.84 mmol) analogously to Example 1. The benzyl protecting group wascleaved in-situ under the reaction conditions. Purification of the crudematerial was performed by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, heptane/TBME containing 5% offormic acid 95:5→100% TBME containing 5% of formic acid). HPLC:^(A)t_(Ret)=2.09 min; API-MS: m/z 410.1 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 3.47 (d, J=19.8, 1H), 3.66-3.72 (m, 6H), 3.87 (d, J=19.7, 1H),5.92 (s, 1H), 6.61 (s, 1H), 6.82-6.89 (m, 2H), 6.95 (s, 1H), 6.97-7.04(m, 2H), 7.26-7.34 (m, 4H), 9.06 (br. s., 1H).

Example 216-(2-Amino-ethoxy)-1-(4-chloro-phenyl)-7-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 20.3 (15 mg, 0.037 mmol) in DMF (0.5 ml)were successively added Cs₂CO₃ (23.8 mg, 0.073 mmol) and(2-bromo-ethyl)-carbamic acid tert-butyl ester (12.3 mg, 0.055 mmol).The reaction mixture was stirred at RT for 30 min and partitionedbetween water and AcOEt. The organic phase was separated, dried overNa₂SO₄, filtered and evaporated to dryness. The resulting yellow residuewas dissolved in DCM (0.5 ml) and treated with TFA (0.028 ml, 0.37mmol). The reaction mixture was stirred at RT for 30 min, evaporated todryness and the resulting crude material was purified by reverse phaseprep-HPLC (Waters system) to yield the title compound (TFA salt, 8.5 mg,0.015 mmol, 41%). HPLC: ^(A)t_(Ret)=1.61 min; API-MS: m/z 453.3 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆): 3.14-3.24 (m, 2H), 3.59 (d, J=19.8, 1H), 3.71(s, 3H), 3.73 (s, 3H), 3.93 (d, J=19.7, 1H), 4.07-4.16 (m, 2H), 6.00 (s,1H), 6.83-6.89 (m, 2H), 6.91 (s, 1H), 6.98-7.04 (m, 2H), 7.08 (s, 1H),7.33 (s, 4H), 7.89 (br. s., 2H).

Example 227-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-ethoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 22.4 (15 mg, 0.033 mmol) in DMF (0.5 ml)were successively added Cs₂CO₃ (21.6 mg, 0.066 mmol) and iodo-ethane(0.004 ml, 0.05 mmol). The reaction mixture was stirred at RT for 3 hand partitioned between water and AcOEt. The organic phase wasseparated, dried over Na₂SO₄, filtered and evaporated to dryness. Theresulting crude material was purified by reverse phase prep-HPLC (Waterssystem) to yield the title compound (6.5 mg, 0.014 mmol, 41%). HPLC:^(A)t_(Ret)=2.92 min; API-MS: m/z 480.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):0.90-1.01 (m, 3H), 1.14-1.24 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.42 (t, J=7.0, 3H), 1.50-1.75 (m, 2H), 3.72 (d,J=20.3, 1H), 3.78 (s, 3H), 3.99-4.12 (m, 3H), 4.17-4.27 (m, 1H), 5.91(s, 1H), 6.78 (d, J=2.9, 1H), 6.85-6.92 (m, 3H), 6.97-7.02 (m, 2H),7.14-7.19 (m, 2H), 7.27-7.32 (m, 2H).

Intermediate 22.1: [3-Benzyloxy-4-((R)-sec-butoxy)-phenyl]-acetonitrile

The title intermediate (519 mg, 1.76 mmol, 84%) was obtained as acolorless foam from (3-benzyloxy-4-hydroxy-phenyl)-acetonitrile (500 mg,2.09 mmol) and (S)-butan-2-ol (0.23 ml, 2.51 mmol) analogously toIntermediate 1.1. Purification of the crude material was performed byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, heptane/TBME 95:5→1:1). TLC: R_(F)=0.84 (heptane/DCM/TBME1:1:2); HPLC: ^(A)t_(Ret)=2.72 min; LC-MS: m/z 296.1 [M+H]⁺; ¹H NMR (400MHz, CDCl₃): 1.00 (t, J=7.3, 3H), 1.32 (d, J=6.1, 3H), 1.60-1.72 (m,1H), 1.75-1.87 (m, 1H), 3.67 (s, 2H), 4.31 (sxt, J=6.1, 1H), 5.14 (s,2H), 6.84-6.95 (m, 3H), 7.30-7.43 (m, 3H), 7.44-7.50 (m, 2H).

Intermediate 22.2: [3-Benzyloxy-4-((R)-sec-butoxy)-phenyl]-acetic acid

A mixture of Intermediate 22.1 (519 mg, 1.76 mmol) in 4M NaOH in water(3 ml) and EtOH (3 ml) was heated at 80° C. and stirred for 14 h. Thereaction mixture was cooled to RT, concentrated under vacuum thenacidified carefully by the addition of 2M HCl in water and extractedwith DCM. The organic fraction was dried over Na₂SO₄, filtered andevaporated to dryness to give the title compound (538 mg, 1.71 mmol,97%) as an orange oil, which was used in the next step without furtherpurification. HPLC: ^(A)t_(Ret)=2.42 min; LC-MS: m/z 313.2 [M−H]⁺; ¹HNMR (400 MHz, CDCl₃): 0.99 (t, J=7.3, 3H), 1.32 (d, J=6.1, 3H),1.59-1.71 (m, 1H), 1.75-1.87 (m, 1H), 3.58 (s, 2H), 4.29 (sxt, J=6.1,1H), 5.12 (s, 2H), 6.82-6.87 (m, 1H), 6.88-6.92 (m, 2H), 7.30-7.34 (m,1H), 7.35-7.41 (m, 2H), 7.43-7.49 (m, 2H).

Intermediate 22.3: 3-Benzyloxy-4-((R)-sec-butoxy)-phenyl]-acetylchloride

The title intermediate (571 mg, 1.71 mmol, quant.) was obtained as anorange oil from Intermediate 22.2 (539 mg, 1.71 mmol) analogously toIntermediate 1.3.

Intermediate 22.4:7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-hydroxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (270 mg, 0.60 mmol, 35%) was obtained as anoff-white foam from Intermediate 20.1 (423 mg, 1.72 mmol) andIntermediate 22.3 (573 mg, 1.72 mmol) analogously to Example 1. Thebenzyl protecting group was cleaved in-situ under the reactionconditions. Purification of the crude material was performed byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, heptane/TBME containing 5% of formic acid 95:5→4:6). TLC:R_(F)=0.76 (heptane/DCM/TBME containing 5% of formic acid 1:1:2); HPLC:^(A)t_(Ret)=2.53 min; API-MS: m/z 452.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):0.88-1.01 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.15-1.29 (2d,J=6.1, 3H, mixture of diastereoisomers), 1.49-1.81 (m, 2H), 3.64 (d,J=20.3, 1H), 3.79 (s, 3H), 3.98 (d, J=20.1, 1H), 4.22-4.31 (m, 1H), 5.89(s, 1H), 6.72 (s, 1H), 6.74-6.78 (m, 1H), 6.87-6.93 (m, 2H), 6.96-7.02(m, 2H), 7.13-7.19 (m, 2H), 7.26-7.33 (m, 2H).

Example 237-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-6-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethoxy]-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 23.1 (15 mg, 0.029 mmol) in DMF (0.5 ml)were successively added 1-methyl-piperazine (0.016 ml, 0.15 mmol), NMM(0.016 ml, 0.15 mmol) and HATU (16.8 mg, 0.044 mmol). The reactionmixture was stirred at RT for 1 h then partitioned between AcOEt andwater. The organic phase was separated, dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byreverse phase prep-HPLC (Waters system) to yield the title compound (TFAsalt, 11.1 mg, 0.016 mmol, 54%). HPLC: ^(A)t_(Ret)=1.92 min; API-MS: m/z592.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.84-0.95 (2t, J=7.3, 3H,mixture of diastereoisomers), 1.11-1.25 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.45-1.70 (m, 2H), 2.81 (s, 3H), 2.88-3.14 (m, 3H),3.29-3.48 (m, 3H), 3.52 (d, J=19.8, 1H), 3.71 (s, 3H), 3.92 (d, J=19.1,1H), 3.99-4.15 (m, 1H), 4.23-4.34 (m, 1H), 4.34-4.47 (m, 1H), 4.81 (s,2H), 6.01 (m, 1H), 6.78 (s, 1H), 6.83-6.90 (m, 2H), 6.98-7.09 (m, 3H),7.29-7.37 (m, 4H).

Intermediate 23.1:[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-3-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-aceticacid

The title compound (116 mg, 0.23 mmol, 90% over 2 steps) was obtained asan off-white solid from Intermediate 22.4 (120 mg, 0.27 mmol) followingthe same 2 steps sequence as described for Example 13. Purification ofthe crude material was performed by precipitation into water andfiltration. HPLC: ^(A)t_(Ret)=2.42 min; API-MS: m/z 509.8 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆): 0.84-0.94 (2t, J=7.4, 3H, mixture ofdiastereoisomers), 1.11-1.22 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.46-1.67 (m, 2H), 3.53 (d, J=19.7, 1H), 3.70 (s,3H), 3.86 (d, J=20.2, 1H), 4.21-4.31 (m, 1H), 4.62 (s, 2H), 5.99 (m,1H), 6.73 (s, 1H), 6.82-6.89 (m, 2H), 7.01-7.06 (m, 3H), 7.29-7.35 (m,4H), 12.87 (br. s., 1H).

Example 241-(4-Chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-7-propoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 24.2 (25 mg, 0.061 mmol) in DMF (0.5 ml)were successively added Cs₂CO₃ (39.7 mg, 0.12 mmol) and 1-iodo-propane(0.015 ml, 0.15 mmol). The reaction mixture was heated at 50° C. andstirred for 3 h, then cooled to RT and partitioned between water andAcOEt. The organic phase was separated, dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byreverse phase prep-HPLC (Waters system) to yield the title compound(12.2 mg, 0.027 mmol, 44%). HPLC: ^(A)t_(Ret)=2.64 min; API-MS: m/z452.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 1.01 (t, J=7.3, 3H), 1.71-1.82(m, 2H), 3.73 (d, J=20.3, 1H), 3.79 (s, 3H), 3.80-3.95 (m, 2H), 3.87 (s,3H), 4.05 (d, J=20.3, 1H), 5.91 (s, 1H), 6.78 (s, 1H), 6.86-6.93 (m,3H), 6.96-7.02 (m, 2H), 7.14-7.19 (m, 2H), 7.30 (m, 2H).

Intermediate 24.1: (4-Benzyloxy-3-methoxy-phenyl)-acetyl chloride

The title intermediate (1.0 g, 3.44 mmol, quant.) was obtained as anorange oil from (4-benzyloxy-3-methoxy-phenyl)-acetic acid (937 mg, 3.44mmol) analogously to Intermediate 1.3.

Intermediate 24.2:1-(4-Chloro-phenyl)-7-hydroxy-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (681 mg, 1.66 mmol, 48%) was obtained as anoff-white solid from Intermediate 20.1 (845 mg, 3.44 mmol) andIntermediate 24.1 (1.0 g, 3.44 mmol) analogously to Example 1. Thebenzyl protecting group was cleaved in-situ under the reactionconditions. Purification of the crude material was performed byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, [heptane/DCM 1:1]/TBME containing 5% of formic acid 95:5→3:7).HPLC: ^(A)t_(Ret)=2.07 min; API-MS: m/z 410.1 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 3.56 (d, J=20.0, 1H), 3.70 (s, 3H), 3.74 (s, 3H), 3.90 (d,J=19.8, 1H), 5.92 (s, 1H), 6.70 (s, 1H), 6.77 (s, 1H), 6.81-6.87 (m,2H), 6.95-7.01 (m, 2H), 7.22-7.27 (m, 2H), 7.28-7.34 (m, 2H), 8.91 (br.s., 1H).

Example 257-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 24.2 (200 mg, 0.49 mmol) in DCM (13 ml)were successively added (S)-butan-2-ol (0.054 ml, 0.59 mmol), supportedPPh₃ (loading 1.52 mmol/g, 963 mg, 1.46 mmol) and DTAD (169 mg, 0.73mmol). The reaction mixture was shaken at RT for 3 h, then filtered andthe resin was washed with DCM. The filtrate was evaporated to drynessand the resulting residue was purified by Combi-Flash Companion™ (IscoInc.) column chromatography (SiO₂; gradient elution, [heptane/DCM1:1]/TBME 95:5→1:1) to yield the title compound (136 mg, 0.29 mmol, 60%)as a colorless foam. TLC: R_(F)=0.39 (heptane/DCM/TBME 1:1:2); HPLC:^(A)t_(Ret)=2.74 min; API-MS: m/z 466.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃):0.93-1.03 (m, 3H, 2 diastereoisomers visible), 1.23-1.35 (m, 3H, 2diastereoisomers visible), 1.59-1.69 (m, 1H), 1.71-1.84 (m, 1H), 3.74(d, J=20.1, 1H), 3.81 (s, 3H), 3.85-3.94 (m, 4H), 4.14-4.24 (m, 1H),5.70 (s, 1H), 6.67 (d, J=4.6, 1H), 6.71 (s, 1H), 6.84-6.91 (m, 2H),6.99-7.10 (m, 4H), 7.23-7.28 (m, 2H).

Example 261-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 26.3 (20 mg, 0.047 mmol) in DCM (1.5 ml)were successively added propan-2-ol (0.011 ml, 0.14 mmol), supportedPPh₃ (loading 1.52 mmol/g, 93 mg, 0.14 mmol) and DTAD (32.7 mg, 0.14mmol). The reaction mixture was shaken at RT for 14 h, then filtered andthe resin was washed with DCM. The filtrate was evaporated to drynessand the resulting residue was purified by reverse phase prep-HPLC(Waters system) to yield the title compound (TFA salt, 17 mg, 0.029mmol, 62%) as a colorless solid. HPLC: ^(A)t_(Ret)=1.88 min; LC-MS: m/z465.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 1.19 (d, J=6.1, 3H), 1.24 (d,J=5.9, 3H), 2.89 (s, 6H), 3.58 (d, J=19.8, 1H), 3.73 (s, 3H), 3.91 (d,J=19.8, 1H), 4.45 (spt, J=5.9, 1H), 5.98 (s, 1H), 6.69-6.80 (m, 2H),6.84 (s, 1H), 6.94-7.00 (m, 2H), 7.03 (s, 1H), 7.35 (s, 4H).

Intermediate 26.1: (4-Hydroxy-3-methoxy-phenyl)-acetic acid

A mixture of (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (2 g,9.51 mmol) and LiOH monohydrate (1.2 g, 28.5 mmol) in MeOH (20 ml) andwater (10 ml) was stirred at RT for 14 h. The reaction mixture wasconcentrated under vacuum, diluted into water and neutralized by theaddition of HCl 2 M in water (14.3 ml). The resulting slurry wasextracted with DCM (3×) and AcOEt (2×) and the combined organicfractions were dried over Na₂SO₄, filtered and evaporated to dryness toyield the crude title compound (1.67 g, 9.17 mmol, 96%) as a brownishsolid, which was used in the next step without further purification.HPLC: ^(A)t_(Ret)=0.77 min; LC-MS: m/z 183.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 3.43 (s, 2H), 3.74 (s, 3H), 6.61-6.66 (m, J=8.1, 2.0, 1H),6.67-6.72 (m, 1H), 6.81 (d, J=2.0, 1H), 8.81 (s, 1H), 12.17 (s, 1H).

Intermediate 26.2: (4-Hydroxy-3-methoxy-phenyl)-acetyl chloride

The title intermediate (1.78 g, 8.89 mmol, quant.) was obtained fromIntermediate 26.1 (1.62 g, 8.89 mmol) analogously to Intermediate 1.3.

Intermediate 26.3:1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-7-hydroxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (1.35 g, 3.19 mmol, 36%) was obtained as a brownishsolid from Intermediate 1.4 (2.3 g, 8.89 mmol) and Intermediate 26.2(1.62 g, 8.9 mmol) analogously to Example 1. Purification of the crudematerial was performed by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, [heptane/DCM 1:1]/TBMEcontaining 5% of 7 M NH₃ in MeOH 95:5→4:6). TLC: R_(F)=0.16(heptane/DCM/TBME containing 5% of 7 M NH₃ in MeOH 1:1:2); HPLC:^(A)t_(Ret)=1.44 min; LC-MS: m/z 423.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 2.89 (s, 6H), 3.56 (d, J=20.1, 1H), 3.76 (s, 3H), 3.91 (d,J=19.8, 1H), 5.91 (s, 1H), 6.70-6.77 (m, 3H), 6.80 (s, 1H), 6.91-6.98(m, 2H), 7.26-7.37 (m, 4H), 8.99 (br. s., 1H).

Example 27

Compounds 27aa to 27 bp were obtained from Intermediate 20.3 (oranalogues prepared similarly) analogously to Example 20 or 21, fromIntermediate 22.4 (or analogues prepared similarly) analogously toExample 22 or 23, from Intermediate 24.2 (or analogues preparedsimilarly) analogously to Example 24 or 25, or from Intermediate 26.3(or analogues prepared similarly) analogously to Example 26.

# Structure Name/HPLC/MS 27aa

1-(4-Chloro-phenyl)-6-(2-dimethylamino-ethoxy)-7-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.65; API-MS: m/z 481.2 [M + H]⁺. 27ab⁽¹⁾

1-(4-Chloro-phenyl)-6-(2-hydroxy-ethoxy)-7-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.99; API-MS: m/z 454.2 [M + H]⁺. 27ac

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-(3-dimethylamino-propoxy)-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.96; API-MS: m/z537.2 [M + H]⁺. 27ad

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-isobutoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3- one. HPLC:^(A)t_(Ret) = 3.29; API-MS: m/z 509.7 [M + H]⁺. 27ae

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-isopropoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 3.06; API-MS: m/z 494.2 [M + H]⁺. 27af

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-6-propoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 3.13; API-MS: m/z 494.3 [M + H]⁺. 27ag

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-(3-hydroxy-propoxy)-2-(4-methoxy-phenyl)-1,4- dihydro-2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 2.48; API-MS: m/z 510.2 [M + H]⁺. 27ah

2-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-3-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-N,N-dimethyl-acetamide. HPLC: ^(A)t_(Ret) = 2.45;API-MS: m/z 538.5 [M + H]⁺. 27ai

2-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-3-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-N-methyl-acetamide. HPLC: ^(A)t_(Ret) = 2.41;API-MS: m/z 524.5 [M + H]⁺. 27aj

1-(4-Chloro-phenyl)-7-isobutoxy-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) =2.84; API-MS: m/z 466.2 [M + H]⁺. 27ak

7-sec-Butoxy-1-(4-chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) =2.76; API-MS: m/z 466.2 [M + H]⁺. 27al

1-(4-Chloro-phenyl)-7-cyclopropylmethoxy-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.61; API-MS: m/z 464.2 [M + H]⁺. 27am

1-(4-Chloro-phenyl)-7-cyclopentyloxy-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3- one. HPLC: ^(A)t_(Ret)= 2.81; API-MS: m/z 478.2 [M + H]⁺. 27an

1-(4-Chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.61; API-MS: m/z 538.6 [M + H]⁺. 27ao

7-((S)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3- one. HPLC:^(A)t_(Ret) = 2.73; API-MS: m/z 466.2 [M + H]⁺. 27ap

1-(4-Chloro-phenyl)-7-(3-hydroxy-propoxy)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.99; API-MS: m/z 468.2 [M + H]⁺. 27aq

1-(4-Chloro-phenyl)-7-(3-dimethylamino-propoxy)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.61; API-MS: m/z 495.2 [M + H]⁺. 27r

1-(4-Chloro-phenyl)-7-(1-ethyl-propoxy)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3- one. HPLC:^(A)t_(Ret) = 2.88; API-MS: m/z 480.2 [M + H]⁺. 27as

7-(3-Amino-propoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.57; API-MS: m/z 467.2 [M + H]⁺. 27at

1-(4-Chloro-phenyl)-7-cyclobutoxy-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) =2.63; API-MS: m/z 464.2 [M + H]⁺. 27au

1-(4-Chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-7-(1-methyl-butoxy)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.90; API-MS: m/z 480.2 [M + H]⁺. 27av

1-(4-Chloro-phenyl)-7-(1,2-dimethyl-propoxy)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.92; API-MS: m/z 480.2 [M + H]⁺. 27aw

7-(3-Amino-1-methyl-propoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.64; API-MS: m/z 481.3 [M + H]⁺. 27ax

1-(4-Chloro-phenyl)-7-cyclohexyloxy-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.22; LC-MS: m/z 505.3 [M + H]⁺. 27ay

7-Benzyloxy-1-(4-chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.07; LC-MS: m/z 513.3 [M + H]⁺. 27az

1-(4-Chloro-phenyl)-7-cyclohexylmethoxy-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.45; LC-MS: m/z 519.3 [M + H]⁺. 27ba

1-(4-Chloro-phenyl)-7-cyclobutylmethoxy-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.17; LC-MS: m/z 491.3 [M + H]⁺. 27bb

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-7-ethoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3- one. HPLC: ^(A)t_(Ret) =1.76; LC-MS: m/z 451.3 [M + H]⁺. 27bc

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-7-isobutoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3- one. HPLC: ^(A)t_(Ret)= 2.13; LC-MS: m/z 479.3 [M + H]⁺. 27bd

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-propoxy-1,4-dihydro-2H-isoquinolin-3- one. HPLC: ^(A)t_(Ret) =1.96; LC-MS: m/z 465.3 [M + H]⁺. 27be

1-(4-Chloro-phenyl)-7-cyclopentylmethoxy-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.31; LC-MS: m/z 505.3 [M + H]⁺. 27bf

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-7-(1-ethyl-propoxy)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.17; LC-MS: m/z 493.3 [M + H]⁺. 27bg

1-(4-Chloro-phenyl)-7-cyclopentyloxy-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.08; LC-MS: m/z 491.2 [M + H]⁺. 27bh

1-(4-Chloro-phenyl)-7-cyclopropylmethoxy-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.92; LC-MS: m/z 477.3 [M + H]⁺. 27bi

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(1-methyl-butoxy)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.19; LC-MS: m/z 493.3 [M + H]⁺. 27bj

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-((R)-2-methoxy-1-methyl-ethoxy)-1,4-dihydro-2H-isoquinolin-3-one HPLC: ^(A)t_(Ret) = 1.77; LC-MS: m/z 495.3[M + H]⁺. 27bk

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-7-(1,3-dimethyl-but-3-enyloxy)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.21; LC-MS: m/z 505.3[M + H]⁺. 27bl

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(1-methyl-but-3-enyloxy)-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 2.09; LC-MS: m/z 491.3 [M + H]⁺. 27bm

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6,7-dimethoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.61; LC-MS: m/z 437.4 [M + H]⁺. 27bn

1-(4-Chloro-phenyl)-7-cyclobutoxy-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.96; LC-MS: m/z 477.4 [M + H]⁺. 27bo

7-((S)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.04; LC-MS: m/z 479.4 [M + H]⁺. 27bp

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(pyridin-4-ylmethoxy)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.22; LC-MS: m/z 514.3 [M + H]⁺. ⁽¹⁾The title compound(11.8 mg, 0.021 mmol, 57% over 2 steps) was obtained from Intermediate20.3 (15 mg, 0.037 mmol) following the same 2 steps sequence asdescribed for Example 15l. Purification of the crude material wasperformed by reverse phase prep-HPLC (Waters system).

Example 281-(4-Chloro-phenyl)-7-isopropylamino-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 28.9 (400 mg, 0.85 mmol) in DCM (5 ml)were successively added AcOH (0.176 ml, 3.07 mmol), acetone (0.125 ml,1.71 mmol) and NaBH(OAc)₃ (651 mg, 3.07 mmol) at RT. The reactionmixture was stirred at RT for 4 h then diluted with DCM and washed witha 2M aqueous Na₂CO₃ solution (2×). The organic phase was dried overNa₂SO₄, filtered and evaporated to dryness. The resulting crude materialwas purified by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, DCM/MeOH 99.5:0.5→9:1) to yield the titlecompound (392 mg, 0.77 mmol, 90%) as a brownish resin. TLC: R_(F)=0.41(DCM/MeOH 9:1); HPLC: ^(A)t_(Ret)=1.30 min; LC-MS: m/z 511.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆): 1.03-1.13 (2d, J=6.2, 6H), 3.03 (s, 3H),3.40-3.55 (m, 2H), 3.77 (d, J=19.6, 1H), 4.58 (s, 2H), 5.34 (d, J=8.1,1H), 5.87 (s, 1H), 6.47 (dd, J=8.2, 2.1, 1H), 6.56-6.64 (m, 3H),6.87-6.94 (m, 3H), 7.15-7.20 (m, 2H), 7.28-7.38 (m, 4H), 8.45-8.50 (m,2H).

Intermediate 28.1: (2-Chloro-5-nitro-phenyl)-(4-chloro-phenyl)-methanol

To a solution of (4-chlorophenyl)magnesium bromide (1M in Et₂O, 81 ml,81 mmol) in THF (200 ml) was added drop wise a solution of2-chloro-5-nitrobenzaldehyde (10 g, 53.9 mmol) in THF (100 ml) at −78°C. (dry ice/acetone bath). After the addition, the reaction mixture wasfurther stirred at −78° C. for 1 h then 10 min at 0° C. (ice bath). Asaturated aqueous NH₄Cl solution (400 ml) was added and the resultingmixture was extracted with AcOEt (2×400 ml). The combined organic layerswere washed with brine then dried over Na₂SO₄, filtered and evaporatedto dryness. The resulting crude material was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,heptane/TBME 95:5→6:4) to yield the title compound (14.4 g, 48.4 mmol,90%) as a beige solid. TLC: R_(F)=0.80 (heptane/DCM/TBME 1:1:2); HPLC:^(A)t_(Ret)=2.43 min; LC-MS: m/z not detected; ¹H NMR (400 MHz, CDCl₃):6.20 (s, 1H), 7.36 (s, 4H), 7.53 (d, J=8.6, 1H), 8.13 (dd, J=8.8, 2.9,1H), 8.66 (d, J=2.7, 1H).

Intermediate 28.2: (2-Chloro-5-nitro-phenyl)-(4-chloro-phenyl)-methanone

To a solution of Intermediate 28.1 (14.07 g, 47.2 mmol) in DCM (236 ml)was added PDC (26.6 g, 70.8 mmol) in one portion at RT and the resultingsuspension was vigorously stirred at RT for 14 h. The reaction mixturewas filtered through a Celite pad, the solids were washed with DCM andthe filtrate evaporated to dryness. The resulting crude material waspurified by Combi-Flash Companion™ (Isco Inc.) column chromatography(gradient elution, heptane/AcOEt 95:5 to 9:1) to yield the titlecompound (11.7 g, 39.5 mmol, 84%) as an orange viscous oil. TLC:R_(F)=0.47 (heptane/AcOEt 4:1); HPLC: ^(A)t_(Ret)=2.64 min; LC-MS: m/z296.5 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃): 7.51 (m, 2H), 7.65-7.81 (m, 3H),8.23-8.39 (m, 2H).

Intermediate 28.3: [2-(4-Chloro-benzoyl)-4-nitro-phenyl]-acetic acidmethyl ester

To a suspension of NaH (60% in mineral oil, 3.46 g, 86 mmol) in DMSO wasslowly added tert-butylmethylmalonate (14.6 ml, 86 mmol) at 0° C. (icebath). After the addition, the reaction mixture was heated at 60° C. andstirred for 30 min then cooled to RT. A solution of Intermediate 28.2(11.63 g, 39.3 mmol) in DMSO (40 ml) was added, then the mixture washeated again at 60° C. and stirred for 1 h30. The reaction mixture wascooled to RT then diluted into Et₂O and washed with brine. The organiclayer was dried over Na₂SO₄, filtered and evaporated to dryness. Theresulting reddish oil was dissolved in DCM (30 ml) and TFA (30 ml) wasslowly added at RT (Warning: important gas evolution occurred!). Thereaction mixture was stirred at RT for 30 min then concentrated undervacuum. The resulting crude material was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (gradient elution,heptane/TBME 95:5 to 100% TBME) to yield the title compound (13.7 g,39.4 mmol, quant.) as an off-white solid. TLC: R_(F)=0.36 (heptane/TBME1:1); HPLC: ^(A)t_(Ret)=2.42 min; LC-MS: m/z 334.4 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆): 3.48 (s, 3H), 4.01 (s, 2H), 7.62-7.69 (m, 2H), 7.74-7.83(m, 3H), 8.19 (d, J=2.4, 1H), 8.42 (dd, J=8.4, 2.6, 1H).

Intermediate 28.4: [2-(4-Chloro-benzoyl)-4-nitro-phenyl]-acetic acid

A suspension of Intermediate 28.3 (13.7 g, 39.4 mmol) and LiOHmonohydrate (8.64 g, 206 mmol) in MeOH (100 ml) and water (50 ml) wasstirred at RT for 1 h then concentrated under vacuum. The resultingresidue was diluted with water and neutralized by the addition of 2M HClin water. The resulting precipitate was filtered, washed with water, anddissolved in DCM. The organic fraction was dried over Na₂SO₄, filteredand evaporated to dryness to yield the crude title compound (10.16 g,31.8 mmol, 81%) as a beige solid. HPLC: ^(A)t_(Ret)=2.06 min; LC-MS: m/z320.5 [M+H]⁺.

Intermediate 28.5:{2-[Chloro-(4-chloro-phenyl)-methyl]-4-nitro-phenyl}-acetic acid ethylester

To a suspension of Intermediate 28.4 (2.5 g, 7.82 mmol) in EtOH (40 ml)was added

NaBH₄ (888 mg, 23.46 mmol) at RT (Warning: important gaz evolutionoccurred!). The resulting red solution was stirred at RT for 15 min thencooled to 0° C. (ice bath) before SOCl₂ (8.56 ml, 117 mmol) wascautiously added. The resulting slurry was stirred at 0° C. for 30 minthen concentrated under vacuum. The resulting residue was diluted withAcOEt and washed with a 2M aqueous Na₂CO₃ solution (2×). The organicphase was dried over Na₂SO₄, filtered and evaporated to dryness. Theresulting crude material was purified by Combi-Flash Companion™ (IscoInc.) column chromatography (gradient elution, heptane/AcOEt 95:5 to1:1) to yield the title compound (2.5 g, 6.79 mmol, 87%) as a yellow oilwhich crystallized on standing into a yellow solid. TLC: R_(F)=0.63(heptane/AcOEt 1:1); HPLC: ^(A)t_(Ret)=2.85 min; ¹H NMR (400 MHz,DMSO-d₆): 1.09 (t, J=7.2, 3H), 3.81-4.04 (m, 4H), 6.91 (s, 1H),7.40-7.50 (m, 4H), 7.61 (d, J=8.6, 1H), 8.21 (dd, J=8.3, 2.2, 1H), 8.34(d, J=2.0, 1H).

Intermediate 28.6: Methyl-(4-nitro-phenyl)-pyridin-4-ylmethyl-amine

To a solution of N-methyl-4-nitroaniline (5 g, 32.9 mmol) in DMF (75 ml)was slowly added NaH (60% in mineral oil, 4.21 g, 105 mmol) at RT(Warning: important gaz evolution occurred!). The suspension wasvigorously stirred at RT for 15 min then cooled to 0° C. (ice bath).4-(Chloromethyl)pyridine hydrochloride (8.09 g, 49.3 mmol) was addedcarefully then the slurry was allowed to warm to RT and further stirredfor 45 min. The reaction mixture was poured into water and extractedwith Et₂O (3×). The combined organic phases were dried over Na₂SO₄,filtered and evaporated to dryness to yield the crude title compound(10.13 g) as an orange solid, which was used in the next step withoutfurther purification. HPLC: ^(A)t_(Ret)=1.01 min; LC-MS: m/z 244.5[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 3.23 (s, 3H), 4.82 (s, 2H), 6.77-6.83(m, 2H), 7.17-7.22 (m, 2H), 8.02-8.08 (m, 2H), 8.49-8.54 (m, 2H).

Intermediate 28.7: N-Methyl-N-pyridin-4-ylmethyl-benzene-1,4-diamine

A suspension of Intermediate 28.6 (10.13 g) and Fe in powder (18.34 g,328 mmol) in AcOH (65.7 ml), water (82 ml) and AcOEt (16.4 ml) washeated at 80° C. and stirred for 30 min. The reaction mixture was cooledto RT and concentrated under vacuum. The resulting aqueous mixture wasbasified by the addition of a 2M aqueous Na₂CO₃ solution until pH 8-9then filtered through a Celite pad and the filter cake was washed withAcOEt. The biphasic filtrate was separated and the organic phase wasdried over Na₂SO₄, filtered and evaporated to dryness. The resultingcrude material was purified by Combi-Flash Companion™ (Isco Inc.) columnchromatography (gradient elution, DCM/7M NH₃ in MeOH 99.7:0.3 to 95:5)to yield the title compound (4.14 g, 19.41 mmol, 59% for 2 steps) as abrownish solid. TLC: R_(F)=0.37 (DCM/7M NH₃ in MeOH 95:5); HPLC:^(A)t_(Ret)=0.73 min; LC-MS: m/z 214.6 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 2.80 (s, 3H), 4.35 (s, 2H), 4.42 (br. s., 2H), 6.44-6.50 (m,2H), 6.51-6.58 (m, 2H), 7.20 (d, J=5.4, 2H), 8.46 (d, J=5.6, 2H).

Intermediate 28.8:1-(4-Chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-7-nitro-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 28.7 (1.46 g, 6.84 mmol) in DCM (10 ml)were successively added DIPEA (1.49 ml, 8.55 mmol) and a solution ofIntermediate 28.5 (2.1 g, 5.70 mmol) in DCM (10 ml) at RT. The reactionmixture was stirred at RT for 45 min then evaporated to dryness. To asolution of the resulting residue in AcOH (20 ml) was added H₂SO₄ (0.456ml, 8.55 mmol) at RT. The mixture was heated at 80° C., stirred for 1 hthen cooled to RT, and concentrated under vacuum. The resulting residuewas diluted with AcOEt and washed with a 2M aqueous Na₂CO₃ solution(2×). The organic phase was dried over Na₂SO₄, filtered and evaporatedto dryness. The resulting crude material was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (gradient elution, DCM/MeOH99.5:0.5 to 9:1) to yield the title compound (2.08 g, 4.17 mmol, 73%) asa brown solid. TLC: R_(F)=0.43 (DCM/MeOH 9:1); HPLC: ^(A)t_(Ret)=1.87min; LC-MS: m/z 499.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): 3.02 (s, 3H),3.86 (d, J=20.3, 1H), 4.15 (d, J=20.3, 1H), 4.58 (s, 2H), 6.34 (s, 1H),6.58-6.64 (m, 2H), 6.90-6.96 (m, 2H), 7.17 (d, J=5.5, 2H), 7.34-7.46 (m,4H), 7.55 (d, J=8.5, 1H), 8.13 (dd, J=8.4, 2.3, 1H), 8.41 (d, J=2.0,1H), 8.44-8.49 (m, 2H).

Intermediate 28.9:7-Amino-1-(4-chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 28.8 (2.08 g, 4.17 mmol) in EtOH (30 ml)was added SnCl₂ dihydrate (9.41 g, 41.7 mmol) at RT. The slurry washeated at 80° C. and vigorously stirred 30 min. The reaction mixture wascooled to RT and poured into NaOH 2M in water (62.5 ml). The resultingslurry was stirred at RT for 10 min then filtered through a Celite padand the filter cake was washed with Et₂O. The biphasic filtrate wasseparated and the aqueous phase further extracted with Et₂O (2×). Thecombined organic fractions were dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byCombi-Flash Companion™ (Isco Inc.) column chromatography (gradientelution, DCM/MeOH 99.5:0.5 to 9:1) to yield the title compound (1.17 g,2.50 mmol, 60%) as a brown solid. TLC: R_(F)=0.43 (DCM/MeOH 9:1); HPLC:^(A)t_(Ret)=1.20 min; LC-MS: m/z 469.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 3.02 (s, 3H), 3.45 (d, J=19.6, 1H), 3.78 (d, J=19.6, 1H), 4.57(s, 2H), 5.03 (br. s., 2H), 5.84 (s, 1H), 6.48 (dd, J=8.2, 1.8, 1H),6.52-6.55 (m, 1H), 6.56-6.64 (m, 2H), 6.84-6.93 (m, 3H), 7.18 (d, J=5.4,2H), 7.24-7.38 (m, 4H), 8.48 (d, J=5.9, 2H).

Example 29N-{1-(4-Chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-3-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl}-propionamide

To a solution of Intermediate 28.9 (30 mg, 0.064 mmol) in MeCN (0.5 ml)were successively added pyridine (0.010 ml, 0.128 mmol) and propionylchloride (0.008 ml, 0.096 mmol) at RT. The reaction mixture was stirredat RT for 30 min then directly subjected to purification by reversephase prep-HPLC (Waters system) to yield the title compound (TFA salt,20.2 mg, 0.032 mmol, 49%) as a yellow solid. HPLC: ^(A)t_(Ret)=1.60 min;LC-MS: m/z 525.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 1.05 (t, J=7.6, 3H),2.28 (q, J=7.6, 2H), 3.07 (s, 3H), 3.61 (d, J=20.1, 1H), 3.95 (d,J=20.1, 1H), 4.78 (s, 2H), 6.01 (s, 1H), 6.58-6.65 (m, 2H), 6.89-6.96(m, 2H), 7.17 (d, J=8.3, 1H), 7.26-7.38 (m, 4H), 7.41 (dd, J=8.3, 1.5,1H), 7.62-7.69 (m, 3H), 8.70-8.76 (m, 2H), 9.89 (s, 1H).

Example 301-(4-Chloro-phenyl)-7-(isopropyl-propyl-amino)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Example 28 (20 mg, 0.039 mmol) in MeCN (0.5 ml) weresuccessively added AcOH (0.007 ml, 0.117 mmol), propionaldehyde (0.009ml, 0.117 mmol) and NaBH(OAc)₃ (24.9 mg, 0.117 mmol) at RT. The reactionmixture was stirred at RT for 3 h30 then directly subjected topurification by reverse phase prep-HPLC (Waters system) to yield thetitle compound (TFA salt, 21 mg, 0.027 mmol, 69%) as a yellow solid.HPLC: ^(A)t_(Ret)=1.37 min; LC-MS: m/z 553.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.86 (t, J=7.3, 3H), 1.11 (d, J=6.7, 3H), 1.14 (d, J=6.6, 3H),1.37-1.51 (m, 2H), 3.00 (s, 3H), 3.04-3.11 (m, 2H), 3.51 (d, J=19.6,1H), 3.75 (d, J=19.6, 1H), 3.86-3.96 (m, 1H), 4.57 (s, 2H), 5.91 (s,1H), 6.61-6.68 (m, 2H), 6.70-6.79 (m, 2H), 6.90-6.96 (m, 2H), 7.00-7.06(m, 1H), 7.21-7.35 (m, 6H), 8.47-8.54 (m, 2H).

Example 311-(4-Chloro-phenyl)-7-[(2-dimethylamino-ethyl)-isopropyl-amino]-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

To a solution of the crude Intermediate 31.2 (138 mg) in MeCN (0.5 ml)were successively added AcOH (0.018 ml, 0.314 mmol), formaldehyde (37%in water, 0.024 ml, 0.314 mmol) and NaBH(OAc)₃ (66.5 mg, 0.314 mmol) atRT. The reaction mixture was stirred at RT for 2 h then directlysubjected to purification by reverse phase prep-HPLC (Waters system) toyield the title compound (TFA salt, 13 mg, 0.016 mmol, 31% over 3 steps)as a light yellow solid. HPLC: ^(A)t_(Ret)=1.48 min; LC-MS: m/z 580.4[M+H]⁺.

Intermediate 31.1:[2-({1-(4-Chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-3-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl}-isopropyl-amino)-ethyl]-carbamicacid tert-butyl ester

The crude title compound (174 mg) was obtained as a brown solid fromExample 28 (80 mg, 0.157 mmol) and N-Boc-2-aminoacetaldehyde (100 mg,0.626 mmol) analogously to Example 30. The crude material was used inthe next step without further purification. HPLC: ^(A)t_(Ret)=1.63 min;LC-MS: m/z 654.5 [M+H]⁺.

Intermediate 31.2:7-[(2-Amino-ethyl)-isopropyl-amino]-1-(4-chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

A solution of the crude Intermediate 31.1 (174 mg) in DCM (2 ml) and TFA(1 ml) was stirred at RT for 1 h30 then evaporated to dryness to yieldthe crude title compound (415 mg) as a dark resin which was used in thenext step without further purification. HPLC: ^(A)t_(Ret)=1.37 min;LC-MS: m/z 554.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 1.10 (t, J=6.8, 6H),2.76-2.90 (m, 2H), 3.07 (s, 3H), 3.28-3.36 (m, 2H), 3.52 (d, J=19.6,1H), 3.80 (d, J=19.6, 1H), 3.97-4.06 (m, 1H), 4.73 (s, 2H), 5.94 (s,1H), 6.59-6.66 (m, 2H), 6.77 (dd, J=8.4, 2.3, 1H), 6.91-6.99 (m, 3H),7.07 (d, J=8.3, 1H), 7.33-7.42 (m, 4H), 7.47-7.53 (m, 2H), 7.71-7.80 (m,2H), 8.66 (d, J=6.1, 2H).

Example 32N-[2-({1-(4-Chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-3-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl}-isopropyl-amino)-ethyl]-acetamide

The title compound (10.8 mg, 0.013 mmol, 25% over 3 steps) was obtainedas a beige solid from the crude Intermediate 31.2 (138 mg) andacetylchloride (0.033 ml, 0.471 mmol) analogously to Example 29.Purification of the crude material was performed by reverse phaseprep-HPLC (Waters system). HPLC: ^(A)t_(Ret)=1.28 min; LC-MS: m/z 596.4[M+H]⁺.

Example 33

Compounds 33a to 33r were obtained from Intermediate 28.9 (or analoguesprepared similarly) analogously to Example 28 or 29, or from Example 28(or analogues prepared similarly) analogously to Example 30, 31 or 32.

# Structure Name/HPLC/MS/NMR 33a

1-(4-Chloro-phenyl)-7-isobutylamino-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H- isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.64; LC-MS: m/z 525.3 [M + H]⁺. 33b

1-(4-Chloro-phenyl)-7-(cyclopentylmethyl-amino)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.72; LC-MS: m/z 551.2 [M +H]⁺. 33c

1-(4-Chloro-phenyl)-7-(1-ethyl-propylamino)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.63; LC-MS: m/z 539.3 [M +H]⁺. 33d

1-(4-Chloro-phenyl)-7-cyclohexylamino-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H- isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.51; LC-MS: m/z 551.3 [M + H]⁺. 33e

7-sec-Butylamino-1-(4-chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H- isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.42; LC-MS: m/z 525.2 [M + H]⁺. 33f

1-(4-Chloro-phenyl)-7-cyclobutylamino-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H- isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.50; LC-MS: m/z 523.2 [M + H]⁺. 33g

1-(4-Chloro-phenyl)-7-cyclopentylamino-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H- isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.47; LC-MS: m/z 537.2 [M + H]⁺. 33h

1-(4-Chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-7-propylamino-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.40; LC-MS: m/z 511.2 [M + H]⁺. 33i

1-(4-Chloro-phenyl)-7-ethylamino-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin- 3-one. HPLC:^(A)t_(Ret) = 1.27; LC-MS: m/z 497.2 [M + H]⁺. 33j

7-Benzylamino-1-(4-chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H- isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.79; LC-MS: m/z 559.2 [M + H]⁺. 33k

1-(4-Chloro-phenyl)-7-(cyclopropylmethyl-amino)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.40; LC-MS: m/z 523.3 [M +H]⁺. 33l

1-(4-Chloro-phenyl)-7-(cyclohexylmethyl-amino)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.87; LC-MS: m/z 565.2 [M +H]⁺. 33m

N-{1-(4-Chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-3-oxo-1,2,3,4-tetrahydro-isoquinolin-7- yl}-acetamide.HPLC: ^(A)t_(Ret) = 1.49; LC-MS: m/z 511.1 [M + H]⁺. 33n

N-{1-(4-Chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-3-oxo-1,2,3,4-tetrahydro-isoquinolin-7- yl}-isobutyramideHPLC: ^(A)t_(Ret) = 1.71; LC-MS: m/z 539.2 [M + H]⁺. 33o

N-{1-(4-Chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-3-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl}-N-isopropyl-acetamide. HPLC: ^(A)t_(Ret) = 1.67; LC-MS: m/z 553.3[M + H]⁺. 33p

N-{1-(4-Chloro-phenyl)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl-3-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl}-N-isopropyl-propionamide. HPLC: ^(A)t_(Ret) = 1.77; LC-MS: m/z 567.3[M + H]⁺. 33q

1-(4-Chloro-phenyl)-7-(isopropyl-methyl-amino)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.27; LC-MS: m/z 525.4 [M +H]⁺. 33r

1-(4-Chloro-phenyl)-7-(ethyl-isopropyl-amino)-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.29; LC-MS: m/z 539.4 [M +H]⁺.

Example 347-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

A reaction flask was charged with CuI (0.51 mg, 0.003 mmol) and K₃PO₄(22.67 mg, 0.11 mmol) then evacuated and backfilled with argon (3times). N,N′-Dimethylethylenediamine (0.006 ml, 0.006 mmol),pyrrolidin-2-one (5 l, 0.064 mmol), Intermediate 34.3 (30 mg, 0.053mmol) and toluene (0.5 ml) were added, the reaction flask was sealed,heated at 80° C. and stirred for 1 h30. The reaction mixture was cooledto RT, filtered through a Celite pad and the solid was washed with MeOH.The filtrate was evaporated to dryness and the resulting residue waspurified by reverse phase prep-HPLC (Waters system) to yield the titlecompound (8 mg, 0.015 mmol, 28%). HPLC: ^(A)t_(Ret)=2.50 min; API-MS:m/z 519.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃): 0.92-1.03 (m, 3H, mixture ofdiastereoisomers), 1.23-1.33 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.56-1.84 (m, 2H), 2.20 (quin, J=7.5, 2H), 2.67 (t,J=8.1, 2H), 3.79 (d, J=19.8, 1H), 3.85-3.97 (m, 6H), 4.20 (sxt, J=6.1,1H), 5.75 (s, 1H), 6.67 (d, J=3.9, 1H), 6.72 (s, 1H), 7.03-7.09 (m, 2H),7.10-7.16 (m, 2H), 7.24-7.30 (m, 2H), 7.58-7.64 (m, 2H).

Intermediate 34.1:[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-(4-iodo-phenyl)-amine

The title compound (2.08 g, 6.10 mmol, 89%) was obtained as a brownishsolid from 4-iodo-phenylamine (1.5 g, 6.85 mmol) and4-chloro-benzaldehyde (963 mg, 6.85 mmol) analogously to Intermediate1.4. ¹H NMR (400 MHz, CDCl₃): 6.94-7.02 (m, 2H), 7.44-7.51 (m, 2H),7.69-7.76 (m, 2H), 7.82-7.89 (m, 2H), 8.40 (s, 1H).

Intermediate 34.2:1-(4-Chloro-phenyl)-7-hydroxy-2-(4-iodo-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (496 mg, 0.98 mmol, 36%) was obtained as a lightyellow solid from Intermediate 34.1 (939 mg, 2.75 mmol) and Intermediate24.1 (799 mg, 2.75 mmol) analogously to Example 1. The benzyl protectinggroup was cleaved in-situ under the reaction conditions. Purification ofthe crude material was performed by Combi-Flash Companion™ (Isco Inc.)column chromatography (SiO₂; gradient elution, [heptane/DCM 1:1]/TBMEcontaining 5% of formic acid 95:5→7:3). TLC: R_(F)=0.40(heptane/DCM/TBME 1:1:2); HPLC: ^(A)t_(Ret)=2.42 min; API-MS: m/z 506.0[M+H]⁺; ¹H NMR (400 MHz, CDCl₃): 3.71 (d, J=19.6, 1H), 3.84 (d, J=19.8,1H), 3.93 (s, 3H), 5.62 (s, 1H), 5.71 (s, 1H), 6.69 (s, 1H), 6.79 (s,1H), 6.88-6.94 (m, 2H), 7.07-7.13 (m, 2H), 7.25-7.31 (m, 2H), 7.65-7.71(m, 2H).

Intermediate 34.3:7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-iodo-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (350 mg, 0.62 mmol, 64%) was obtained as a yellowfoam from Intermediate 34.2 (496 mg, 0.98 mmol) and (S)-butan-2-ol (0.11ml, 1.18 mmol) analogously to Example 25. Purification of the crudematerial was performed by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, [heptane/DCM 1:1]/TBME95:5→4:6). TLC: R_(F)=0.64 (heptane/DCM/TBME 1:1:2); HPLC:^(A)t_(Ret)=3.06 min; API-MS: m/z 562.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):0.89-1.00 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.14-1.25 (2d,J=6.1, 3H, mixture of diastereoisomers), 1.50-1.75 (m, 2H), 3.75 (d,J=20.3, 1H), 3.86 (s, 3H), 4.02 (d, J=20.3, 1H), 4.19-4.29 (m, 1H), 5.99(s, 1H), 6.81 (d, J=3.4, 1H), 6.87-6.95 (m, 3H), 7.15-7.21 (m, 2H),7.28-7.34 (m, 2H), 7.68-7.75 (m, 2H).

Example 357-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-pyrazol-1-yl-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

A reaction flask was charged with Intermediate 34.3 (25 mg, 0.044 mmol),1H-pyrazole (4.5 mg, 0.067 mmol), Cu₂O (0.3 mg, 0.002 mmol),salicylaldoxime (1.2 mg, 0.009 mmol) and Cs₂CO₃ (29.0 mg, 0.089 mmol)then evacuated and backfilled with argon (3 times). MeCN (0.5 ml) wasadded, the reaction flask was sealed, heated at 80° C. and stirred for14 h. The reaction mixture was cooled to RT, diluted with DCM andfiltered through a Celite pad. The solid was washed with DCM, thefiltrate was evaporated to dryness and the resulting residue waspurified by reverse phase prep-HPLC (Waters system) to yield the titlecompound (12.5 mg, 0.02 mmol, 46%). HPLC: ^(A)t_(Ret)=2.71 min; API-MS:m/z 503.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.83-0.93 (m, 3H, mixtureof diastereoisomers), 1.10-1.21 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.44-1.67 (m, 2H), 3.63 (d, J=20.0, 1H), 3.73 (s,3H), 3.88-3.97 (m, 1H), 4.15-4.28 (m, 1H), 6.13 (d, J=3.3, 1H),6.49-6.52 (m, 1H), 6.84 (s, 1H), 7.00 (d, J=6.7, 1H), 7.23-7.29 (m, 2H),7.31-7.34 (m, 4H), 7.70 (d, J=1.8, 1H), 7.74-7.79 (m, 2H), 8.42 (d,J=2.5, 1H).

Example 367-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

A mixture of Intermediate 34.3 (20 mg, 0.036 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.36 mg,0.053 mmol) and aqueous Na₂CO₃ 2M (0.062 ml, 0.125 mmol) in DME (0.6 ml)was evacuated under vacuum and backfilled with argon (3 times).PdCl₂(PPh₃)₂ (1.25 mg, 0.0018 mmol) was added, the reaction flask wassealed and irradiated in a microwave oven at 150° C. for 15 min. Thereaction mixture was cooled to RT, diluted into AcOEt and washed withwater. The organic layer was dried over Na₂SO₄, filtered and evaporatedto dryness. The crude material was purified by reverse phase prep-HPLC(Waters system) to yield the title compound (TFA salt, 5 mg, 0.008 mmol,23%). HPLC: ^(A)t_(Ret)=2.38 min; LC-MS: m/z 502.2 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆): 0.84-0.92 (2t, J=7.5, 3H, mixture of diastereoisomers),1.11-1.21 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.45-1.67 (m,2H), 3.61 (d, J=20.0, 1H), 3.73 (s, 3H), 3.92 (dd, J=19.8, 3.7, 1H),4.18-4.28 (m, 1H), 6.10 (d, J=4.1, 1H), 6.85 (s, 1H), 7.01-7.04 (m, 1H),7.10-7.15 (m, 2H), 7.33-7.37 (m, 4H), 7.53-7.58 (m, 2H), 8.02 (br. s.,2H).

Example 37

Compounds 37a to 37c were obtained from Intermediate 34.3 (or analoguesprepared similarly) analogously to Example 34, 35 or 36.

# Structure Name/HPLC/MS 37a

N-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]- phenyl}-acetamide. HPLC:^(A)t_(Ret) = 2.33; API-MS: m/z 493.2 [M + H]⁺. 37b

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(2-oxo-azetidin-1-yl)-phenyl]-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.49; API-MS: m/z 505.1 [M + H]⁺. 37c⁽¹⁾

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.14; LC-MS: m/z 530.2[M + H]⁺. ⁽¹⁾The title compound (TFA salt, 15 mg, 0.023 mmol, 44%) wasobtained from Intermediate 34.3 (30 mg, 0.053 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(11.9 mg, 0.053 mmol) and Pd(PPh₃)₄ (3.1 mg, 0.003 mmol) as a catalystanalogously to Example 36. Purification of the crude material wasperformed by reverse phase prep-HPLC (Waters system).

Example 384-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-N-ethyl-N-methyl-benzamide

To a solution of Intermediate 38.3 (25 mg, 0.052 mmol) in DMF (0.5 ml)were successively added ethyl-methyl-amine (0.013 ml, 0.156 mmol), NMM(0.017 ml, 0.156 mmol) and HATU (23.77 mg, 0.063 mmol) at RT. Thereaction mixture was stirred at RT for 2 h then directly subjected topurification by reverse phase prep-HPLC (Waters system) to yield thetitle compound (12.7 mg, 0.024 mmol, 47%). HPLC: ^(A)t_(Ret)=2.46 min;LC-MS: m/z 521.7 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 0.89-1.00 (2t, J=7.5,3H, mixture of diastereoisomers), 1.11-1.28 (m, 6H), 1.50-1.77 (m, 2H),2.95-3.10 (m, 3H), 3.53-3.62 (m, 1H), 3.77 (d, J=20.3, 1H), 3.86 (s,3H), 4.05 (d, J=20.3, 1H), 4.20-4.30 (m, 1H), 6.07 (br. s., 1H),6.80-6.85 (m, 1H), 6.90 (s, 1H), 7.18-7.33 (m, 6H), 7.37-7.46 (m, 2H).

Intermediate 38.1:4-{[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-amino}-benzoic acid methylester

The title compound (2.35 g, 8.59 mmol, 87%) was obtained as a lightyellow solid from methyl 4-aminobenzoate (1.5 g, 9.92 mmol) and4-chloro-benzaldehyde (1.40 g, 9.92 mmol) analogously to Intermediate1.4. ¹H NMR (400 MHz, CDCl₃): 3.95 (s, 3H), 7.20-7.25 (m, 2H), 7.46-7.52(m, 2H), 7.84-7.91 (m, 2H), 8.07-8.13 (m, 2H), 8.42 (s, 1H).

Intermediate 38.2:4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzoicacid methyl ester

The title compound (780 mg, 1.58 mmol, 64%) was obtained fromIntermediate 38.1 (672 mg, 2.45 mmol) and Intermediate 1.3 (630 mg, 2.45mmol) analogously to Example 1. Purification of the crude material wasperformed by reverse phase column chromatography (C18; gradient elution,water containing 0.5% TFA/MeCN 95:5→1:9).

HPLC: ^(A)t_(Ret)=2.75 min; LC-MS: m/z 494.3 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃): 0.94-1.03 (2t, J=7.5, 3H, mixture of diastereoisomers),1.26-1.35 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.56-1.85 (m,2H), 3.72-3.87 (m, 2H), 3.88 (s, 3H), 3.93 (s, 3H), 4.17-4.28 (m, 1H),5.82 (s, 1H), 6.73 (s, 1H), 6.75 (d, J=4.9, 1H), 7.06-7.12 (m, 2H),7.25-7.32 (m, 4H), 8.01-8.08 (m, 2H).

Intermediate 38.3:4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzoicacid

A mixture of Intermediate 38.2 (400 mg, 0.81 mmol) and LiOH monohydrate(170 mg, 4.05 mmol) in MeOH (8 ml) and water (2 ml) was stirred at RTfor 5 h. The reaction mixture was concentrated under vacuum, dilutedinto water and neutralized by the addition of HCl 2 M in water. Theresulting slurry was extracted with DCM (3×) and the combined organicfractions were dried over Na₂SO₄, filtered and evaporated to dryness toyield the crude title compound (461 mg, quant.) as an orange oil, whichwas used in the next step without further purification. HPLC:^(A)t_(Ret)=2.41 min; LC-MS: m/z 480.5 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃):0.95-1.03 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.29-1.34 (2d,J=6.1, 3H, mixture of diastereoisomers), 1.58-1.85 (m, 2H), 3.72-3.87(m, 2H), 3.88 (s, 3H), 4.19-4.28 (m, 1H), 5.83 (s, 1H), 6.73 (s, 1H),6.77 (d, J=4.9, 1H), 7.07-7.13 (m, 2H), 7.26-7.35 (m, 4H), 8.05-8.11 (m,2H).

Example 39(2S,4R)-1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzoyl}-4-hydroxy-pyrrolidine-2-carboxylicacid methylamide

To a solution of Intermediate 39.1 (30 mg, 0.051 mmol) in DMF (0.5 ml)were successively added methylamine (2M solution in THF, 0.25 ml, 0.50mmol), NMM (0.017 ml, 0.156 mmol) and HATU (28.9 mg, 0.076 mmol) at RT.The reaction mixture was stirred at RT for 2 h then diluted into AcOEtand washed with a 2M aqueous Na₂CO₃ solution. The organic layer wasdried over Na₂SO₄, filtered and evaporated to dryness. The crudematerial was purified by reverse phase prep-HPLC (Waters system) toyield the title compound (19.9 mg, 0.033 mmol, 65%) as a yellow solid.HPLC: ^(A)t_(Ret)=2.00 min; LC-MS: m/z 606.2 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆): 0.83-0.94 (2t, J=7.5, 3H, mixture of diastereoisomers),1.11-1.22 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.47-1.68 (m,2H), 1.79-1.88 (m, 1H), 2.04-2.12 (m, 1H), 2.55-2.60 (m, 2H), 3.26 (d,J=11.0, 1H), 3.51-3.77 (m, 5H), 3.89 (dd, J=19.8, 7.3, 1H), 4.17-4.29(m, 2H), 4.46 (t, J=8.5, 1H), 6.18 (d, J=2.9, 1H), 6.86 (s, 1H), 7.07(d, J=10.5, 1H), 7.24-7.29 (m, 2H), 7.30-7.38 (m, 3H), 7.52-7.58 (m,2H), 7.81-7.89 (m, 1H).

Intermediate 39.1:(2S,4R)-1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzoyl}-4-hydroxy-pyrrolidine-2-carboxylicacid

To a solution of Intermediate 38.3 (73 mg, 0.15 mmol) in DCM (1 ml) weresuccessively added oxalylchloride (0.020 ml, 0.23 mmol) and a catalyticamount of DMF (0.001 ml, 0.015 mmol) at 0° C. (ice bath). The reactionmixture was stirred at 0° C. for 30 min then DIPEA (0.106 ml, 0.608mmol) and (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl esterhydrochloride (41.4 mg, 0.228 mmol) were successively added. Thereaction mixture was allowed to warm to RT and stirred for 1 h. A 2Maqueous KOH solution was added then the heterogeneous mixture wasstirred for 30 min and extracted with Et₂O. The organic layer was driedover Na₂SO₄, filtered and evaporated to dryness to yield the crude titlecompound (71 mg, 0.12 mmol, 79%) as a yellow resin, which was used inthe next step without further purification. HPLC: ^(A)t_(Ret)=2.04 min;LC-MS: m/z 593.4 [M+H]⁺.

Example 40

Compounds 40a to 40l were obtained from Intermediate 38.3 (or analoguesprepared similarly) analogously to Example 38 or 39.

# Structure Name/HPLC/MS/NMR 40a

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(piperidine-1-carbonyl)-phenyl]-1,4-dihydro-2H- isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 2.63; LC-MS: m/z 547.5 [M + H]⁺. 40b

4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-N-methyl- benzamide. HPLC:^(A)t_(Ret) = 2.29; LC-MS: m/z 493.4 [M + H]⁺. 40c

4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-N,N-diethyl- benzamide. HPLC:^(A)t_(Ret) = 2.58; LC-MS: m/z 535.5 [M + H]⁺. 40d

4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-N,N-dimethyl- benzamide. HPLC:^(A)t_(Ret) = 2.35; LC-MS: m/z 507.4 [M + H]⁺. 40e

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(pyrrolidine-1-carbonyl)-phenyl]-1,4-dihydro-2H- isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 2.47; LC-MS: m/z 533.5 [M + H]⁺. 40f

4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzamide. HPLC: ^(A)t_(Ret) =2.19; LC-MS: m/z 479.4 [M + H]⁺. 40g

4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-5-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-N-methyl-N-pyridin-4-yl-benzamide. HPLC: ^(A)t_(Ret) = 1.98; LC-MS: m/z 570.3 [M +H]⁺. 40h

4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-N-pyridin-4-yl- benzamide. HPLC:^(A)t_(Ret) = 2.04; LC-MS: m/z 556.3 [M + H]⁺. 40i

4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-N-pyridin-3-yl- benzamide. HPLC:^(A)t_(Ret) = 1.99; LC-MS: m/z 556.3 [M + H]⁺. 40j

(S)-1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzoyl}-pyrrolidine-2-carboxylic acid methylamide. HPLC: ^(A)t_(Ret) =2.18; LC-MS: m/z 590.3 [M + H]⁺. 40k

(R)-1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzoyl}-pyrrolidine-2-carboxylic acid methylamide. HPLC: ^(A)t_(Ret) =2.18; LC-MS: m/z 590.2 [M+H]⁺. 40l

(2R,4S)-1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzoyl}-4-hydroxy-pyrrolidine-2-carboxylic acid methylamide. HPLC:^(A)t_(Ret) = 1.99; LC-MS: m/z 606.3 [M + H]⁺.

Example 417-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-hydroxymethyl-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 38.2 (50 mg, 0.10 mmol) in THF (1 ml) weresuccessively added LiBH₄ (6.6 mg, 0.30 mmol) and MeOH (0.012 ml, 0.30mmol) at RT. The reaction mixture was stirred at RT for 2 h thenquenched cautiously by the addition of HCl 2M in water, diluted into DCMand washed with Na₂CO₃ 2M in water. The aqueous layer was furtherextracted with DCM (2×) and the combined organic fractions were driedover Na₂SO₄, filtered and evaporated to dryness. The resulting crudematerial was purified by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, [heptane/DCM 1:1]/TBME 95:5→100%TBME) to yield the title compound (22 mg, 0.047 mmol, 47%) as a foam.TLC: R_(F)=0.13 (heptane/DCM/TBME 1:1:2); HPLC: ^(A)t_(Ret)=2.33 min;LC-MS: m/z 466.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃): 0.93-1.03 (2t, J=7.5,3H, mixture of diastereoisomers), 1.24-1.34 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.61-1.86 (m, 2H), 3.76 (d, J=19.8, 1H), 3.84-3.92(m, 4H), 4.15-4.26 (m, 1H), 4.70 (s, 2H), 5.76 (s, 1H), 6.68-6.74 (m,2H), 7.05-7.11 (m, 2H), 7.12-7.17 (m, 2H), 7.24-7.30 (m, 2H), 7.34-7.40(m, 2H).

Example 427-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 42.3 (25 mg, 0.055 mmol) in DCM (1 ml)were successively added AcOH (0.009 ml, 0.15 mmol),pyridine-4-carbaldehyde (0.006 ml, 0.061 mmol) and NaBH(OAc)₃ (19.4 mg,0.091 mmol) at RT. The reaction mixture was stirred for 2 h, thenadditional AcOH (0.008 ml, 0.14 mmol), formaldehyde (37% in water, 0.008ml, 0.11 mmol) and additional NaBH(OAc)₃ (17 mg, 0.083 mmol) were added.The reaction mixture was stirred at RT for 2 h then water was added andthe two phases were separated. The aqueous layer was extracted with DCM(2×) and the combined organic fractions were evaporated to dryness. Theresulting residue was purified by reverse phase prep-HPLC (Waterssystem) to yield the title compound (TFA salt, 10.8 mg, 0.016 mmol,29%). HPLC: ^(A)t_(Ret)=2.05 min; LC-MS: m/z 556.3 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆): 0.83-0.94 (m, 3H, mixture of diastereoisomers), 1.09-1.22(2d, J=6.1, 3H, mixture of diastereoisomers), 1.43-1.68 (m, 2H), 3.03(s, 3H), 3.56 (d, J=19.8, 1H), 3.72 (s, 3H), 3.83-3.93 (m, 1H),4.16-4.30 (m, 1H), 4.58 (s, 2H), 5.93-5.98 (m, 1H), 6.57-6.64 (m, 2H),6.83 (s, 1H), 6.87-6.95 (m, 2H), 7.03 (d, J=6.6, 1H), 7.18 (d, J=5.4,2H), 7.34 (s, 4H), 8.48 (d, J=4.9, 2H).

Intermediate 42.1:[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-(4-nitro-phenyl)-amine

The title compound (2.27 g, 8.69 mmol, 80%) was obtained as a yellowsolid from 4-nitro-phenylamine (1.5 g, 10.86 mmol) and4-chloro-benzaldehyde (1.53 g, 10.86 mmol) analogously to Intermediate1.4. ¹H NMR (400 MHz, CDCl₃): 7.23-7.31 (m, 2H), 7.48-7.54 (m, 2H),7.85-7.92 (m, 2H), 8.26-8.34 (m, 2H), 8.42 (s, 1H).

Intermediate 42.2:7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-nitro-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (700 mg, 1.46 mmol, 47%) was obtained as a yellowfoam from Intermediate 42.1 (812 mg, 3.12 mmol) and Intermediate 1.3(800 mg, 3.12 mmol) analogously to Example 1. Purification of the crudematerial was performed by reverse phase prep-HPLC (Waters system). HPLC:^(A)t_(Ret)=2.81 min; LC-MS: m/z 481.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃):0.96-1.04 (m, 3H, mixture of diastereoisomers), 1.28-1.35 (2d, J=6.1,3H, mixture of diastereoisomers), 1.60-1.87 (m, 2H, mixture ofdiastereoisomers), 3.75-3.80 (m, 2H), 3.88 (s, 3H), 4.19-4.31 (m, 1H),5.85 (s, 1H), 6.73 (s, 1H), 6.80 (d, J=4.9, 1H), 7.09-7.15 (m, 2H),7.29-7.34 (m, 2H), 7.39-7.46 (m, 2H), 8.20-8.27 (m, 2H).

Intermediate 42.3:2-(4-Amino-phenyl)-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

In a sealed reaction flask, a mixture of Intermediate 42.2 (700 mg, 1.46mmol) and Fe (813 mg, 14.6 mmol) in AcOH (2.8 ml), water (4 ml) andAcOEt (0.8 ml) was heated at 80° C. and stirred for 1 h. The suspensionwas cooled to RT, neutralized by the addition of a saturated aqueousNaHCO₃ solution to pH 7 and filtered through a Celite pad. The solid waswashed with AcOEt and the biphasic filtrate was transferred into aseparating funnel. The aqueous layer was separated and further extractedwith AcOEt (3×). The combined organic fractions were dried over Na₂SO₄,filtered and evaporated to dryness to yield the crude title compound(651 mg, 1.44 mmol, 99%) as a yellow foam, which was used in the nextstep without further purification. HPLC: ^(A)t_(Ret)=1.88 min; LC-MS:m/z 451.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃): 0.91-1.02 (2t, J=7.5, 3H,mixture of diastereoisomers), 1.21-1.32 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.54-1.83 (m, 2H), 3.83 (d, J=20.3, 1H), 3.89 (s,3H), 3.97 (d, J=20.1, 1H), 4.12-4.23 (m, 1H), 5.69 (s, 1H), 6.61 (d,J=4.6, 1H), 6.72 (s, 1H), 6.81-6.93 (m, 4H), 6.99-7.04 (m, 2H),7.23-7.28 (m, 2H).

Example 43N-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-N-methyl-acetamide

The title compound (50.7 mg, 0.10 mmol, 57%) was obtained fromIntermediate 43.3 (50 mg, 0.17 mmol) and Intermediate 1.3 (44.8 mg, 0.17mmol) analogously to Example 1. Purification of the crude material wasperformed by reverse phase prep-HPLC (Waters system). HPLC:^(A)t_(Ret)=2.37 min; LC-MS: m/z 507.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃):0.94-1.03 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.26-1.34 (2d,J=6.1, 3H, mixture of diastereoisomers), 1.56-1.84 (m, 2H), 1.93 (s,3H), 3.28 (s, 3H), 3.78 (d, J=19.8, 1H), 3.88 (d, J=19.6, 1H), 3.88 (s,3H), 4.17-4.26 (m, 1H), 5.79 (br. s., 1H), 6.71-6.76 (m, 2H), 7.09-7.14(m, 2H), 7.17-7.32 (m, 6H).

Intermediate 43.1: N-Methyl-N-(4-nitro-phenyl)-acetamide

To a solution of N-methyl-4-nitroaniline (200 mg, 1.31 mmol) in THF (5ml) were successively added Et₃N (0.364 ml, 2.63 mmol), acetyl chloride(0.14 ml, 1.97 mmol) and DMAP (8.0 mg, 0.066 mmol) at RT. The reactionmixture was stirred at RT for 2 h then diluted into AcOEt and washedwith water. The organic layer was dried over Na₂SO₄, filtered andevaporated to dryness to yield the crude title compound (275 mg) as abrownish solid, which was used in the next step without furtherpurification. HPLC: ^(A)t_(Ret)=1.17 min; LC-MS: m/z 195.4 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃): 2.05 (br. s., 3H), 3.37 (s, 3H), 7.36-7.46 (m,2H), 8.27-8.36 (m, 2H).

Intermediate 43.2: N-(4-Amino-phenyl)-N-methyl-acetamide

A solution of Intermediate 43.1 (275 mg, 1.232 mmol) in EtOH (5 ml) wasdegassed under vacuum and backfilled with argon. Pd/C (1.31 mg, 0.012mmol) and ammonium formate (155 mg, 2.46 mmol) were successively addedand the heterogeneous mixture was well stirred at RT for 2 h thenfiltered over a Celite pad and the catalyst washed with DCM. Thefiltrate was evaporated to dryness and the resulting crude material waspurified by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, [heptane/DCM 1:1]/TBME containing 5% of 7 M NH₃in MeOH 95:5→100% TBME containing 5% of 7 M NH₃ in MeOH) to yield thetitle compound (190 mg, 1.16 mmol, 94%) as a yellow oil. TLC: R_(F)=0.35(heptane/DCM/TBME containing 5% of 7 M NH₃ in MeOH 1:1:2); HPLC:^(B)t_(Ret)=0.17 and 0.24 min; API-MS: m/z 165.1 [M+H]⁺; ¹H NMR (400MHz, CDCl₃): 1.87 (s, 3H), 3.22 (s, 3H), 6.67-6.73 (m, 2H), 6.94-6.99(m, 2H).

Intermediate 43.3:N-(4-{[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-amino}-phenyl)-N-methyl-acetamide

The title compound (160 mg, 0.56 mmol, 92%) was obtained as a yellowsolid from Intermediate 43.2 (100 mg, 0.61 mmol) and4-chloro-benzaldehyde (86 mg, 0.61 mmol) analogously to Intermediate1.4. ¹H NMR (400 MHz, CDCl₃): 1.93 (s, 3H), 3.31 (s, 3H), 7.19-7.30 (m,4H), 7.45-7.52 (m, 2H), 7.84-7.92 (m, 2H), 8.45 (s, 1H).

Example 44N-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-N-cyclopentylmethyl-acetamide

To a solution of Intermediate 44.1 (24 mg, 0.045 mmol) in THF (1 ml)were successively added Et₃N (0.012 ml, 0.090 mmol), DMAP (0.28 mg,0.002 mmol) and acetyl chloride (0.007 ml, 0.090 mmol) at RT. Thereaction mixture was stirred at RT for 2 h, diluted in DCM and washedwith water. The organic layer was dried over Na₂SO₄, filtered andevaporated to dryness. The crude material was purified by reverse phaseprep-HPLC (Waters system). HPLC: ^(A)t_(Ret)=2.89 min; LC-MS: m/z 575.4[M+H]⁺; ¹H NMR (400 MHz, CDCl₃): 0.94-1.03 (2t, J=7.5, 3H, mixture ofdiastereoisomers), 1.18-1.26 (m, 2H), 1.26-1.34 (2d, J=6.1, 3H, mixtureof diastereoisomers), 1.47-1.84 (m, 8H), 1.88 (s, 3H), 1.97-2.06 (m,1H), 3.66-3.73 (m, 2H), 3.75-3.91 (m, 2H), 3.89 (s, 3H), 4.17-4.26 (m,1H), 5.81 (s, 1H), 6.71-6.76 (m, 2H), 7.08-7.13 (m, 2H), 7.14-7.20 (m,2H), 7.22-7.32 (m, 4H).

Intermediate 44.1:7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(cyclopentylmethyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 42.3 (25 mg, 0.044 mmol) in DCM (1 ml)were successively added AcOH (0.006 ml, 0.11 mmol),cyclopentanecarbaldehyde (0.006 ml, 0.053 mmol) and NaBH(OAc)₃ (14.1 mg,0.066 mmol) at RT. The reaction mixture was stirred at RT for 2 h thenNa₂CO₃ 2 M in water was added, the two phases were separated and theaqueous layer was further extracted with DCM (2×). The combined organicfractions were evaporated to dryness to yield the crude title compound(23.6 mg, 0.044 mmol, quant.) as a brownish solid. HPLC:^(A)t_(Ret)=2.57 min; LC-MS: m/z 533.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃):0.93-1.02 (m, 3H), 1.23-1.33 (m, 5H), 1.51-1.88 (m, 8H), 2.11-2.22 (m,1H), 3.01 (d, J=7.3, 2H), 3.74 (d, J=19.8, 1H), 3.85-3.92 (m, 4H),4.14-4.24 (m, 1H), 5.68 (s, 1H), 6.52-6.58 (m, 2H), 6.66 (d, J=4.2, 1H),6.70 (s, 1H), 6.85-6.90 (m, 2H), 7.05-7.10 (m, 2H), 7.22-7.27 (m, 2H).

Example 457-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(methyl-piperidin-3-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 42.3 (25 mg, 0.055 mmol) in DCM (0.5 ml)were successively added AcOH (0.006 ml, 0.111 mmol), tert-butyl3-formylpiperidine-1-carboxylate (13.0 mg, 0.061 mmol) and NaBH(OAc)₃(23.5 mg, 0.111 mmol) at RT. The reaction mixture was stirred at RT for1 h, then diluted with DCM and washed with water. The organic phase wasdried over Na₂SO₄, filtered and evaporated to dryness. The resultingyellow resin was dissolved in DCM (0.5 ml) then AcOH (0.006 ml, 0.111mmol), formaldehyde (37% in water, 0.008 ml, 0.111 mmol) and NaBH(OAc)₃(23.5 mg, 0.111 mmol) were successively added at RT. The reactionmixture was stirred at RT for 1 h, then diluted with DCM and washed withwater. The organic phase was dried over Na₂SO₄, filtered and evaporatedto dryness. The resulting yellow resin was dissolved in DCM (1 ml) andTFA (0.021 ml, 0.272 mmol) was added at RT. The reaction mixture wasstirred at RT for 30 min then evaporated to dryness. The resulting crudematerial was purified by reverse phase prep-HPLC (Waters system) toyield the title compound (TFA salt, 7 mg, 0.01 mmol, 19%) as a colorlesssolid. HPLC: ^(A)t_(Ret)=2.11 min; LC-MS: m/z 562.6 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆): 0.83-0.95 (2t, J=7.5, 3H, mixture of diastereoisomers),1.10-1.26 (m, 4H), 1.44-1.69 (m, 3H), 1.69-1.84 (m, 2H), 2.01-2.15 (m,1H), 2.59-2.80 (m, 2H), 2.89 (s, 3H), 3.10-3.26 (m, 4H), 3.58 (d,J=19.8, 1H), 3.73 (s, 3H), 3.87-3.97 (m, 1H), 4.17-4.31 (m, 1H),5.92-5.99 (m, 1H), 6.58-6.66 (m, 2H), 6.84 (s, 1H), 6.89-6.96 (m, 2H),6.99-7.05 (m, 1H), 7.36 (s, 4H).

Example 467-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4[methyl-(1-methyl-piperidin-3-ylmethyl)-amino]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Example 45 (TFA salt, 7 mg, 0.01 mmol) in DCM (0.5 ml)were successively added AcOH (0.001 ml, 0.021 mmol), formaldehyde (37%in water, 0.002 ml, 0.021 mmol) and NaBH(OAc)₃ (4.4 mg, 0.021 mmol) atRT. The reaction mixture was stirred at RT for 1 h, then diluted intoDCM and washed with a 2M aqueous Na₂CO₃ solution. The organic phase wasdried over Na₂SO₄, filtered and evaporated to dryness. The crudematerial was purified by reverse phase prep-HPLC (Waters system) toyield the title compound (TFA salt, 7.4 mg, 0.01 mmol, quant.) as acolorless solid. HPLC: ^(A)t_(Ret)=2.11 min; LC-MS: m/z 576.3 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆): 0.83-0.92 (2t, J=7.5, 3H, mixture ofdiastereoisomers), 1.10-1.20 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.44-1.67 (m, 4H), 1.69-1.87 (m, 2H), 2.04-2.19 (m,1H), 2.65-2.81 (m, 5H), 2.84-2.93 (m, 3H), 3.08-3.19 (m, 1H), 3.22-3.41(m, 3H), 3.56 (d, J=20.0, 1H), 3.72 (s, 3H), 3.91 (d, J=20.0, 1H),4.17-4.27 (m, 1H), 5.91-5.96 (m, 1H), 6.58-6.63 (m, 2H), 6.83 (s, 1H),6.88-6.94 (m, 2H), 6.98-7.02 (m, 1H), 7.32-7.37 (m, 4H).

Example 477-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(methyl-piperidin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

The title compound (TFA salt, 27 mg, 0.04 mmol, 36%) was obtained as alight yellow solid from Intermediate 42.3 (50 mg, 0.111 mmol) and benzyl4-formylpiperidine-1-carboxylate (30.2 mg, 0.122 mmol) analogously toExample 45. Cleavage of the benzyloxy carbamate protecting group wasachieved by hydrogenolysis with ammonium formate (1.5 equiv.) and Pd/C(0.05 equiv.) as a catalyst in EtOH (0.1 M) at RT for 2 h. Purificationof the crude material was performed by reverse phase prep-HPLC (Waterssystem). HPLC: ^(A)t_(Ret)=2.01 min; LC-MS: m/z 562.5 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆): 0.83-0.95 (2t, J=7.5, 3H, mixture ofdiastereoisomers), 1.10-1.22 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.23-1.37 (m, 2H), 1.45-1.69 (m, 2H), 1.71-1.82 (m,2H), 1.87-1.98 (m, 1H), 2.75-2.88 (m, 2H), 2.91 (s, 3H), 3.16-3.30 (m,4H), 3.60 (d, J=20.1, 1H), 3.73 (s, 3H), 3.86-3.95 (m, 1H), 4.18-4.31(m, 1H), 5.95 (d, J=2.9, 1H), 6.56-6.64 (m, 2H), 6.84 (s, 1H), 6.88-6.96(m, 2H), 7.03 (d, J=5.9, 1H), 7.36 (s, 4H), 8.06-8.20 (m, 1H), 8.41-8.54(m, 1H).

Example 482-{4-[(1-Acetyl-piperidin-4-ylmethyl)-methyl-amino]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Example 47 (TFA salt, 12 mg, 0.018 mmol) in DCM (0.5ml) were successively added pyridine (0.009 ml, 0.107 mmol) and aceticanhydride (0.002 ml, 0.026 mmol) at RT. The reaction mixture was stirredat RT for 1 h then diluted with AcOEt and washed with water and brine.The organic phase was dried over Na₂SO₄, filtered and evaporated todryness. The resulting crude material was purified by reverse phaseprep-HPLC (Waters system) to yield the title compound (TFA salt, 7.1 mg,0.01 mmol, 55%) as a colorless solid. HPLC: ^(A)t_(Ret)=2.24 min; LC-MS:m/z 604.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): 0.82-0.92 (2t, J=7.5, 3H,mixture of diastereoisomers), 0.93-1.03 (m, 1H), 1.05-1.21 (m, 4H),1.45-1.65 (m, 4H), 1.82-1.92 (m, 1H), 1.95 (s, 3H), 2.37-2.45 (m, 1H),2.84-2.98 (m, 4H), 3.12-3.20 (m, 2H), 3.56 (d, J=19.8, 1H), 3.72 (s,3H), 3.74-3.81 (m, 1H), 3.84-3.92 (m, 1H), 4.18-4.28 (m, 1H), 4.31-4.39(m, 1H), 5.94 (d, J=4.1, 1H), 6.55-6.62 (m, 2H), 6.82 (s, 1H), 6.86-6.92(m, 2H), 7.02 (d, J=7.3, 1H), 7.34 (s, 4H).

Example 497-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(1-methanesulfonyl-piperidin-4-ylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Example 47 (20 mg, 0.036 mmol) in MeCN (0.5 ml) weresuccessively added Et₃N (0.015 ml, 0.11 mmol) and methanesulfonylchloride (8.2 mg, 0.071 mmol) at RT. The reaction mixture was stirred atRT for 1 h then directly subjected to purification by reverse phaseprep-HPLC (Waters system) to yield the title compound (TFA salt, 16.1mg, 0.021 mmol, 60%) as a colorless solid. HPLC: ^(A)t_(Ret)=2.53 min;LC-MS: m/z 640.4 [M+H]⁺.

Example 504-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid dimethylamide

To a solution of Example 47 (20 mg, 0.036 mmol) in MeCN (0.5 ml) weresuccessively added Et₃N (0.015 ml, 0.11 mmol) and dimethylcarbamoylchloride (0.007 ml, 0.071 mmol) at RT. The reaction mixture was stirredat RT for 30 min then directly subjected to purification by reversephase prep-HPLC (Waters system) to yield the title compound (TFA salt,17.4 mg, 0.023 mmol, 65%) as a colorless solid. HPLC: ^(A)t_(Ret)=2.39min; LC-MS: m/z 633.4 [M+H]⁺.

Example 512-{4-[(Trans-4-amino-cyclohexylmethyl)-methyl-amino]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 51.1 (1.35 g, 2.0 mmol) in DCM (16 ml) wasadded TFA (8.0 ml, 104 mmol) at RT. The reaction mixture was stirred atRT for 30 min then evaporated to dryness. The resulting crude materialwas dissolved in AcOEt and washed with a 2M aqueous Na₂CO₃ solution(2×). The organic layer was dried over Na₂SO₄, filtered and evaporatedto dryness. The resulting crude material was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,DCM/7M NH₃ in MeOH 99.5:0.5→9:1) to yield the title compound (761 mg,1.32 mmol, 66%) as a brown solid. TLC: R_(F)=0.26 (DCM/7M NH₃ in MeOH9:1); HPLC: ^(A)t_(Ret)=1.91 min; LC-MS: m/z 576.4 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆): 0.84-0.97 (m, 6H), 1.11-1.23 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.43-1.78 (m, 8H), 2.39-2.48 (m, 1H), 2.87 (s, 3H),3.04-3.14 (m, 2H), 3.57 (d, J=19.8, 1H), 3.73 (s, 3H), 3.89 (d, J=19.8,1H), 4.18-4.31 (m, 1H), 5.95 (d, J=3.4, 1H), 6.51-6.61 (m, 2H), 6.84 (s,1H), 6.86-6.93 (m, 2H), 7.04 (d, J=5.9, 1H), 7.35 (s, 4H).

Intermediate 51.1:{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-carbamicacid tert-butyl ester

To a solution of Intermediate 42.3 (1.0 g, 2.23 mmol) in DCM (13 ml)were successively added AcOH (0.26 ml, 4.46 mmol),(trans)-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (557 mg,2.45 mmol) and NaBH(OAc)₃ (945 mg, 4.46 mmol) at RT. The reactionmixture was stirred at RT for 1 h, then diluted with DCM and washed witha 2M aqueous Na₂CO₃ solution (2×). The organic phase was dried overNa₂SO₄, filtered and evaporated to dryness. The resulting yellow solidwas dissolved in DCM (13 ml) then AcOH (0.25 ml, 4.44 mmol),formaldehyde (37% in water, 0.33 ml, 4.44 mmol) and NaBH(OAc)₃ (940 mg,4.44 mmol) were successively added at RT. The reaction mixture wasstirred at RT for 1 h, then diluted with DCM and washed with a 2Maqueous Na₂CO₃ solution (2×). The organic phase was dried over Na₂SO₄,filtered and evaporated to dryness. The resulting crude material waspurified by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, [heptane/DCM 1:1]/TBME containing 5% of 7M NH₃in MeOH 95:5→100% TBME containing 55 of 7M NH₃ in MeOH) to yield thetitle compound (1.35 g, 2.0 mmol, 90%) as a yellow solid. TLC:R_(F)=0.32 (heptane/DCM/TBME containing 1% of 7M NH₃ in MeOH 1:1:2);HPLC: ^(A)t_(Ret)=2.80 min; LC-MS: m/z 676.6 [M+H]⁺.

Example 527-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(trans-4-ethylamino-cyclohexylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Example 51 (60 mg, 0.10 mmol) in DCM (1.5 ml) weresuccessively added AcOH (0.06 ml, 1.04 mmol), acetaldehyde (0.032 ml,0.57 mmol) and NaBH(OAc)₃ (221 mg, 1.04 mmol) at RT. The reactionmixture was stirred at RT for 14 h, diluted with DCM and washed with a2M aqueous Na₂CO₃ solution (2×). The organic phase was dried overNa₂SO₄, filtered and evaporated to dryness to yield the crude titlecompound (55 mg, 0.091 mmol, 88%) as a yellow solid which was used inthe next step without further purification. HPLC: ^(A)t_(Ret)=1.97 min;LC-MS: m/z 604.3 [M+H]⁺.

Example 537-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-{[4-(ethyl-methyl-amino)-trans-cyclohexylmethyl]-methyl-amino}-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Example 52 (13.8 mg, 0.023 mmol) in MeCN (0.5 ml) weresuccessively added AcOH (0.003 ml, 0.046 mmol), formaldehyde (37% inwater, 0.003 ml, 0.046 mmol) and NaBH(OAc)₃ (9.7 mg, 0.046 mmol) at RT.The reaction mixture was stirred at RT for 2 h then directly subjectedto purification by reverse phase prep-HPLC (Waters system) to yield thetitle compound (TFA salt, 7.4 mg, 0.010 mmol, 44%) as a colorless solid.HPLC: ^(A)t_(Ret)=2.01 min; LC-MS: m/z 618.4 [M+H]⁺.

Example 54

Compounds 54aa to 54ce were obtained from Intermediate 42.3 (oranalogues prepared similarly), Example 47 (or analogues preparedsimilarly), Example 51 (or analogues prepared similarly) or Example 52(or analogues prepared similarly), analogously to Intermediate 44.1,Example 42, 46, 48, 49, 50, 52, or 53.

# Structure Name/HPLC/MS 54aa

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-diethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)tRet = 2.01; LC-MS: m/z 507.1 [M + H]⁺. 54ab

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(cyclopentylmethyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.52;LC-MS: m/z 547.6 [M + H]⁺. 54ac

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-(isopropyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.02; LC-MS: m/z 507.5[M + H]⁺. 54ad

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(cyclopentyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.11; LC-MS: m/z533.5 [M + H]⁺. 54ae

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(cyclohexyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.22; LC-MS: m/z547.5 [M + H]⁺. 54af

7-((R)-sec-Butoxy)-2-[4-(sec-butyl-methyl-amino)-phenyl]-1-(4-chloro-phenyl)-6-methoxy-1,4- dihydro-2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 2.19; LC-MS: m/z 521.5 [M + H]⁺. 54ag

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(cyclopropylmethyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.12;LC-MS: m/z 519.4 [M + H]⁺. 54ah

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(cyclohexylmethyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.85;LC-MS: m/z 561.4 [M + H]⁺. 54ai

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(isobutyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.57; LC-MS: m/z 521.4[M + H]⁺. 54aj

2-[4-(Benzyl-methyl-amino)-phenyl]-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4- dihydro-2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 2.81; LC-MS: m/z 555.4 [M + H]⁺. 54ak

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(ethyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.01; LC-MS: m/z 493.4[M + H]⁺. 54al

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-ethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.99; LC-MS: m/z 479.6 [M + H]⁺. 54am

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-dipropylamino-phenyl)-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.28; LC-MS: m/z 535.6 [M + H]⁺. 54an

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(cyclobutyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.08; LC-MS: m/z519.4 [M + H]⁺. 54ao

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(2-fluorobenzyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.99; LC-MS: m/z573.2 [M + H]⁺. 54ap

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(2,3-difluoro-benzyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 3.13;LC-MS: m/z 591.2 [M + H]⁺. 54aq

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[methyl-(3-trifluoromethyl-benzyl)-amino]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one HPLC: ^(A)t_(Ret) =3.21; LC-MS: m/z 623.2 [M + H]⁺. 54ar

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) =3.23; LC-MS: m/z 623.2 [M + H]⁺. 54as

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(3-fluoro-benzyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 3.00; LC-MS: m/z573.2 [M+H]⁺. 54at

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(methyl-pyridin-3-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.05;LC-MS: m/z 556.2 [M + H]⁺. 54au

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(4-fluoro-benzyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.84; LC-MS: m/z573.2 [M + H]⁺. 54av

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(3,4-difluoro-benzyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 3.06;LC-MS: m/z 591.2 [M + H]⁺. 54aw

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[(pyridin-4-ylmethyl)-amino]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.97;LC-MS: m/z 542.5 [M + H]⁺. 54ax

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(cyclopropylmethyl-pyridin-4-ylmethyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3- one. HPLC: ^(A)t_(Ret) =2.23; LC-MS: m/z 596.5 [M + H]⁺. 54ay

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(ethyl-pyridin-4-ylmethyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.13;LC-MS: m/z 570.3 [M + H]⁺. 54az

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[(2-morpholin-4-yl-ethyl)-pyridin-4-ylmethyl-amino]-phenyl}-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.72; LC-MS: m/z 655.4 [M + H]⁺. 54ba

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(methyl-pyrimidin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one HPLC: ^(A)t_(Ret) =2.48; LC-MS: m/z 557.1 [M + H]⁺. 54bb

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(3-fluoro-pyridin-4-ylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.40;LC-MS: m/z 574.2 [M + H]⁺. 54bc

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(methyl-thiophen-3-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) =2.58; LC-MS: m/z 561.2 [M + H]⁺. 54bd

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[methyl-(3-methyl-3H-imidazol-4-ylmethyl)-amino]-phenyl}-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.04; LC-MS: m/z 559.2 [M + H]⁺. 54be

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(furan-3-ylmethyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.40;LC-MS: m/z 545.2 [M + H]⁺. 54bf

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[methyl-(2-morpholin-4-yl-ethyl)-amino]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) =2.03; LC-MS: m/z 578.3 [M + H]⁺. 54bg

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[methyl-(1-methyl-piperidin-4-ylmethyl)-amino]-phenyl}-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.04; LC-MS: m/z 576.3 [M + H]⁺. 54bh

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[methyl-(4-propylamino-trans-cyclohexylmethyl)-amino]-phenyl}-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 2.03; LC-MS: m/z 618.5 [M + H]⁺. 54bi⁽¹⁾

N-{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexyl}-acetamide. HPLC:^(A)t_(Ret) = 2.13; LC-MS: m/z 618.3 [M + H]⁺. 54bj

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(4-dimethylamino-trans-cyclohexylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.98; LC-MS: m/z 604.3 [M + H]⁺. 54bk

2-{4-[(Trans-4-amino-cyclohexylmethyl)-methyl-amino]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3- one. HPLC: ^(A)t_(Ret) =1.91; LC-MS: m/z 576.3 [M + H]⁺. 54bl⁽¹⁾

N-{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexyl}-acetamide. HPLC:^(A)t_(Ret) = 2.15; LC-MS: m/z 618.3 [M + H]⁺. 54bm

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(4-dimethylamino-trans-cyclohexylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.89; LC-MS: m/z 604.3 [M + H]⁺. 54bn

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[methyl-(1-propionyl-piperidin-4-ylmethyl)-amino]-phenyl}-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.41; LC-MS: m/z 618.3 [M + H]⁺. 54bo

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-{methyl-[1-(3-methyl-butyryl)-piperidin-4-ylmethyl]-amino}-phenyl)-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 2.66; LC-MS: m/z 646.5 [M + H]⁺. 54bp

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(1-isobutyryl-piperidin-4-ylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3- one. HPLC: ^(A)t_(Ret) =2.54; LC-MS: m/z 632.5 [M + H]⁺. 54bq

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(1-cyclopropanecarbonyl-piperidin-4-ylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.47; LC-MS: m/z 630.4 [M + H]⁺. 54br

7-((R)-sec-Butoxy)-2-{4-[(1-butyryl-piperidin-4-ylmethyl)-methyl-amino]-phenyl}-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin- one. HPLC: ^(A)t_(Ret) =2.54; LC-MS: m/z 632.4 [M + H]⁺. 54bs⁽¹⁾

N-{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-3-methyl-butyramide. HPLC: ^(A)t_(Ret) = 2.45; LC-MS: m/z660.5 [M + H]⁺. 54bt⁽¹⁾

N-{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexyl}-isobutyramide.HPLC: ^(A)t_(Ret) = 2.36; LC-MS: m/z 646.4 [M + H]⁺. 54bu⁽¹⁾

N-{4-[({4-[7-((R)-sec-Butoxy-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl}-methyl-amino)-methyl]-trans- cyclohexyl}-propionamide. HPLC:^(A)t_(Ret) = 2.25; LC-MS: m/z 632.4 [M + H]⁺. 54bv⁽¹⁾

N-{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexyl}-butyramide. HPLC:^(A)t_(Ret) = 2.35; LC-MS: m/z 646.4 [M + H]⁺. 54bw⁽¹⁾

N-{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexyl}-methanesulfonamide.HPLC: ^(A)t_(Ret) = 2.33; LC-MS: m/z 654.3 [M + H]⁺. 54bx⁽¹⁾

3-{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexyl}-1,1-dimethyl-urea.HPLC: ^(A)t_(Ret) = 2.20; LC-MS: m/z 647.4 [M + H]⁺. 54by

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(1-cyclobutanecarbonyl-piperidin-4-ylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.61; LC-MS: m/z 644.5 [M + H]⁺. 54bz⁽¹⁾

N-{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl}-methyl-amino)-methyl]-trans- cyclohexyl}-N-ethyl-acetamide.HPLC: ^(A)t_(Ret) = 2.42; LC-MS: m/z 646.4 [M + H]⁺. 54ca⁽¹⁾

N-{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-N-ethyl-methanesulfonamide. HPLC: ^(A)t_(Ret) = 2.62; LC-MS:m/z 682.4 [M + H]⁺. 54cb⁽¹⁾

1-{4-[({4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-1-ethyl-3,3-dimethyl-urea. HPLC: ^(A)t_(Ret) = 2.58; LC-MS:m/z 675.5 [M + H]⁺. 54cc

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(trans-4-dipropylamino-cyclohexylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.26; LC-MS: m/z 659.5 [M + H]⁺. 54cd

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-{(trans-4-(isobutyl-methyl-amino)-cyclohexylmethyl]-methyl-amino}-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.13;LC-MS: m/z 646.4 [M + H]⁺. 54ce

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-{[trans-4-(isopropyl-methyl-amino)-cyclohexylmethyl]-methyl-amino}-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.05;LC-MS: m/z 632.4 [M + H]⁺. ⁽¹⁾Title compounds were obtained from thecorresponding amine analogously to Example 48, 49 or 50 using acylchlorides, sulfonyl chlorides or carbamoyl chlorides.

Example 557-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(1-pyrolidin-1-yl-ethyl)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one.(Methode A)

To a solution of Intermediate 55.2 (35 mg, 0.073 mmol) in MeOH (1 ml)were successively added AcOH (0.017 ml, 0.29 mmol), pyrrolidine (0.018ml, 0.22 mmol) and NaBH₃CN (13.8 mg, 0.22 mmol) at RT. The reactionmixture was stirred at RT for 2 h then Na₂CO₃ 2M in water and DCM wereadded. The two phases were separated, the aqueous layer was furtherextracted with DCM (2×) and the combined organic fractions were driedover Na₂SO₄, filtered and evaporated to dryness. The crude material waspurified by reverse phase prep-HPLC (Waters system) to yield the titlecompound (24.1 mg, 0.037 mmol, 51%). HPLC: ^(A)t_(Ret)=2.01 min; LC-MS:m/z 533.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 0.89-1.00 (2t, J=7.5, 3H,mixture of diastereoisomers), 1.14-1.25 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.50-1.71 (m, 2H), 1.70-1.76 (m, 3H), 1.86-2.00 (m,1H), 2.01-2.28 (m, 3H), 2.92-3.17 (m, 2H), 3.19-3.29 (m, 1H), 3.73-3.82(m, 2H), 3.86 (s, 3H), 4.06 (d, J=20.5, 1H), 4.18-4.29 (m, 1H),4.34-4.44 (m, 1H), 6.06 (s, 1H), 6.78-6.83 (m, 1H), 6.90 (s, 1H),7.19-7.25 (m, 2H), 7.26-7.34 (m, 4H), 7.46-7.52 (m, 2H).

Intermediate 55.1:1-(4-{[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-amino}-phenyl)-ethanone

The title compound (460 mg, 1.80 mmol, 49%) was obtained as a lightyellow solid from 1-(4-amino-phenyl)-ethanone (500 mg, 3.7 mmol) and4-chloro-benzaldehyde (520 mg, 3.7 mmol) analogously to Intermediate1.4. ¹H NMR (400 MHz, CDCl₃): 2.64 (s, 3H), 7.22-7.27 (m, 2H), 7.47-7.53(m, 2H), 7.85-7.92 (m, 2H), 8.00-8.06 (m, 2H), 8.43 (s, 1H).

Intermediate 55.2:2-(4-Acetyl-phenyl)-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (286 mg, 0.60 mmol, 62%) was obtained as a yellowfoam from Intermediate 55.1 (248 mg, 0.96 mmol) and Intermediate 1.3(247 mg, 0.96 mmol) analogously to Example 1. Purification of the crudematerial was performed by reverse phase column chromatography (C18;gradient elution, water containing 0.5% TFA/MeCN 95:5→3:7). HPLC:^(A)t_(Ret)=2.63 min; LC-MS: m/z 478.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.85-0.95 (2t, J=7.5, 3H, mixture of diastereoisomers),1.13-1.23 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.46-1.69 (m,2H), 2.55 (s, 3H), 3.66 (d, J=19.8, 1H), 3.74 (s, 3H), 3.90 (dd, J=19.8,3.9, 1H), 4.20-4.31 (m, 1H), 6.25 (d, J=3.4, 1H), 6.88 (s, 1H), 7.10 (d,J=7.1, 1H), 7.32-7.42 (m, 6H), 7.91-7.97 (m, 2H).

Example 567-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(1-morpholin-4-yl-ethyl)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one.(Methode B)

To a solution of Intermediate 55.2 (30 mg, 0.063 mmol) in THF (0.5 ml)were successively added morpholine (0.016 ml, 0.188 mmol) and Ti(OiPr)₄(0.056 ml, 0.188 mmol) at RT. The reaction mixture was heated at reflux,stirred for 14 h and cooled to RT. MeOH (0.2 ml) followed by NaBH₄ (2.4mg, 0.063 mmol) were added and the mixture was stirred at RT for 1 h.Celite and water were added, the heterogenous mixture was vigorouslystirred for 15 min, filtered and the filter cake was washed with AcOEt.The filtrate was washed with a 2M aqueous Na₂CO₃ solution and theorganic phase was dried over Na₂SO₄, filtered and evaporated to dryness.The resulting crude material was purified by reverse phase prep-HPLC(Waters system) to yield the title compound (TFA salt, 19.8 mg, 0.038mmol, 48%) as a colorless solid. HPLC: ^(A)t_(Ret)=1.91 min; LC-MS: m/z549.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 0.89-1.00 (2t, J=7.5, 3H, mixtureof diastereoisomers), 1.14-1.26 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.50-1.73 (m, 2H), 1.76 (t, J=6.4, 3H), 2.93-3.20 (m,3H), 3.60-3.84 (m, 3H), 3.79 (d, J=20.3, 1H), 3.86 (s, 3H), 3.94-4.16(m, 2H), 4.07 (d, J=20.5, 1H), 4.18-4.29 (m, 1H), 4.43-4.52 (m, 1H),6.06 (br. s., 1H), 6.78-6.83 (m, 1H), 6.90 (s, 1H), 7.19-7.26 (m, 2H),7.28-7.35 (m, 4H), 7.48-7.55 (m, 2H).

Example 577-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(1-hydroxy-ethyl)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 55.2 (25 mg, 0.052 mmol) in MeOH (1 ml)was added

NaBH₄ (4 mg, 0.11 mmol) at RT. The reaction mixture was stirred at RTfor 2 h and concentrated under vacuum. The resulting residue wasdissolved in DCM and washed with water. The organic layer was dried overNa₂SO₄, filtered and evaporated to dryness. The crude material waspurified by reverse phase prep-HPLC (Waters system) to yield the titlecompound (11 mg, 0.021 mmol, 39%). HPLC: ^(A)t_(Ret)=2.42 min; LC-MS:m/z 480.5 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆): 0.84-0.93 (2t, J=7.5, 3H,mixture of diastereoisomers), 1.11-1.21 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.28 (d, J=6.6, 3H), 1.45-1.67 (m, 2H), 3.59 (d,J=19.7, 1H), 3.72 (s, 3H), 3.89 (dd, J=19.6, 3.6, 1H), 4.18-4.29 (m,1H), 4.64-4.70 (m, 1H), 6.07 (d, J=4.3, 1H), 6.84 (s, 1H), 7.06 (d,J=7.8, 1H), 7.08-7.12 (m, 2H), 7.26-7.31 (m, 2H), 7.33-7.38 (m, 4H).

Example 58N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-ethyl-acetamide

To a solution Intermediate 58.1 (272 mg, 0.54 mmol) in DCM (5 ml) weresuccessively added pyridine (0.22 ml, 2.68 mmol) and acetic anhydride(0.061 ml, 0.64 mmol) at RT. The reaction mixture was stirred at RT for1 h, diluted into AcOEt and washed with water and brine. The organicphase was dried over Na₂SO₄, filtered and evaporated to dryness. Theresulting crude material was purified by Combi-Flash Companion™ (IscoInc.) column chromatography (SiO₂; gradient elution, DCM/[DCM/MeOH 9:1]95:5→1:1) to yield the title compound (215 mg, 0.39 mmol, 73%) as ayellow resin. TLC: R_(F)=0.31 (DCM/MeOH 95:5); HPLC: ^(A)t_(Ret)=2.54min; LC-MS: m/z 549.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.74-0.96 (m,6H), 1.10-1.23 (m, 3H, mixture of diastereoisomers), 1.38-1.71 (m, 5H),2.02-2.14 (m, 3H), 2.82-3.26 (m, 2H), 3.58-3.67 (m, 1H), 3.74 (s, 3H),3.85-3.95 (m, 1H), 4.17-4.30 (m, 1H), 5.04-5.74 (m, 1H, mixture ofdiastereoisomers), 6.07-6.15 (m, 1H), 6.86 (s, 1H), 7.02-7.08 (m, 1H),7.10-7.21 (m, 2H), 7.22-7.31 (m, 2H), 7.31-7.39 (m, 4H).

Intermediate 58.1:7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(1-ethylamino-ethyl)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 55.2 (500 mg, 1.05 mmol) in dry THF (5 ml)were successively added Ti(OiPr)₄ (0.929 ml, 3.14 mmol) and ethylamine(2M solution in THF, 2.62 ml, 5.23 mmol) at RT. The reaction mixture washeated at reflux for 3 h then cooled to RT. NaBH₃CN (197 mg, 3.14 mmol)was added and the reaction mixture was stirred at RT for 14 h. Celiteand water were added, the heterogenous mixture was vigorously stirredfor 15 min, filtered and the filter cake was washed with AcOEt. Thefiltrate was washed with a 2M aqueous Na₂CO₃ solution and the organicphase was dried over Na₂SO₄, filtered and evaporated to dryness. Theresulting crude material was purified by Combi-Flash Companion™ (IscoInc.) column chromatography (SiO₂; gradient elution, heptane/TBMEcontaining 5% of 7M NH₃ in MeOH 95:5→100% of TBME containing 5% of 7MNH₃ in MeOH) to yield the title compound (272 mg, 0.54 mmol, 51%) as ayellow foam. HPLC: ^(A)t_(Ret)=1.95 min; LC-MS: m/z 507.2 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆): 0.83-0.98 (m, 6H), 1.12-1.22 (m, 3H), 1.45-1.68 (m,3H), 1.80-1.94 (m, 1H), 2.20-2.38 (m, 3H), 3.54-3.67 (m, 2H), 3.72 (s,3H), 3.80-3.88 (m, 1H), 4.17-4.30 (m, 1H), 6.05-6.11 (m, 1H), 6.84 (s,1H), 7.05-7.13 (m, 3H), 7.23-7.30 (m, 2H), 7.35 (s, 4H).

Example 59 1-Acetyl-piperidine-4-carboxylic acid(1-{4-[17-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethyl-amide

To a solution of Intermediate 58.1 (25 mg, 0.049 mmol) in DMF (0.5 ml)were successively added 1-acetylpiperidine-4-carboxylic acid (16.9 mg,0.099 mmol), NMM (0.016 ml, 0.148 mmol) and HATU (28.1 mg, 0.074 mmol)at RT. The reaction mixture was heated at 50° C. and stirred for 24 hthen cooled to RT, diluted with AcOEt and washed with a 2M aqueousNa₂CO₃ solution. The organic phase was dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byreverse phase prep-HPLC (Waters system) to yield the title compound (8.6mg, 0.013 mmol, 26%) as a colorless solid. HPLC: ^(A)t_(Ret)=2.47 min;LC-MS: m/z 660.6 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 0.87-1.07 (m, 6H),1.11-1.27 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.48-1.87 (m,9H), 2.10-2.15 (m, 3H), 2.60-2.79 (m, 1H), 2.83-2.97 (m, 1H), 2.98-3.27(m, 2H), 3.71-3.82 (m, 1H), 3.86 (s, 3H), 3.89-4.11 (m, 2H), 4.16-4.30(m, 1H), 4.48-4.66 (m, 1H), 5.30-5.45 (m, 1H), 5.80-5.93 (m, 1H),5.97-6.08 (m, 1H), 6.79 (d, J=3.4, 1H), 6.89 (s, 1H), 7.10-7.22 (m, 4H),7.26-7.37 (m, 4H).

Example 60 Piperidine-4-carboxylic acid(1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethyl-amide

To a solution of Intermediate 60.1 (13.7 mg, 0.019 mmol) in DCM (1 ml)was added TFA (0.058 ml, 0.76 mmol) at RT. The reaction mixture wasstirred for 1 h then evaporated to dryness. The resulting crude materialwas purified by reverse phase prep-HPLC (Waters system) to yield thetitle compound (TFA salt, 8.2 mg, 0.011 mmol, 58%) as a colorless solid.HPLC: ^(A)t_(Ret)=2.01 min; LC-MS: m/z 618.7 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD): 0.84-1.04 (m, 6H), 1.10-1.25 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.45-1.76 (m, 5H), 1.83-2.07 (m, 4H), 2.89-3.54 (m,5H), 3.69-3.81 (m, 1H), 3.85 (s, 3H), 3.99-4.11 (m, 1H), 4.15-4.31 (m,1H), 5.27-5.41 (m, 1H), 5.77-5.90 (m, 1H), 5.95-6.05 (m, 1H), 6.72-6.82(m, 1H), 6.89 (s, 1H), 7.08-7.41 (m, 8H).

Intermediate 60.1:4-[(1-{-4-[7-(R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethyl-carbamoyl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound (15 mg, 0.02 mmol, 40%) was obtained as a colorlesssolid from Intermediate 58.1 (25 mg, 0.049 mmol) andpiperidine-1,4-dicarboxylic acid mono-tert-butyl ester (22.6 mg, 0.099mmol) analogously to Example 59. Purification of the crude material wasperformed by reverse phase prep-HPLC (Waters system). HPLC:^(A)t_(Ret)=3.07 min; LC-MS: m/z 718.8 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):0.86-1.06 (m, 6H), 1.11-1.27 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.48 (s, 9H), 1.51-1.78 (m, 9H), 2.70-3.26 (m, 4H),3.71-3.81 (m, 1H), 3.86 (s, 3H), 3.98-4.31 (m, 4H), 5.28-5.42 (m, 1H),5.80-5.91 (m, 1H), 5.96-6.06 (m, 1H), 6.77-6.80 (m, 1H), 6.89 (s, 1H),7.09-7.21 (m, 4H), 7.26-7.36 (m, 4H).

Example 617-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[1-(piperidin-4-ylamino)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 61.1 (20 mg, 0.030 mmol) in DCM (0.5 ml)was added TFA (0.023 ml, 0.300 mmol) at RT. The reaction mixture wasstirred at RT for 30 min then evaporated to dryness. The resulting crudematerial was purified by reverse phase prep-HPLC (Waters system) toyield the title compound (TFA salt, 7 mg, 0.01 mmol, 34%) as a yellowsolid. HPLC: ^(A)t_(Ret)=1.69 min; LC-MS: m/z 562.3 [M+H]⁺; ¹H NMR (400MHz, CD₃OD): 0.89-1.00 (2t, J=7.5, 3H, mixture of diastereoisomers),1.14-1.26 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.49-1.78 (m,5H), 1.79-1.99 (m, 2H), 2.18-2.30 (m, 1H), 2.34-2.47 (m, 1H), 2.92-3.10(m, 2H), 3.24-3.35 (m, 2H), 3.45-3.61 (m, 2H), 3.79 (d, J=20.3, 1H),3.86 (s, 3H), 4.09 (d, J=20.8, 1H), 4.18-4.30 (m, 1H), 4.56-4.66 (m,1H), 6.05 (s, 1H), 6.79-6.83 (m, 1H), 6.90 (s, 1H), 7.21-7.26 (m, 2H),7.27-7.35 (m, 4H), 7.49-7.56 (m, 2H).

Intermediate 61.1:4-(1-{-4-[7-(R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethylamino)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of Intermediate 55.2 (136 mg, 0.285 mmol) in THF (1 ml)were successively added tert-butyl 4-aminopiperidine-1-carboxylate (171mg, 0.854 mmol) and Ti(OiPr)₄ (0.253 ml, 0.854 mmol) at RT. The reactionmixture was heated at reflux, stirred for 14 h and cooled to RT. MeOH(0.2 ml) followed by NaBH₄ (10.76 mg, 0.285 mmol) were added and themixture was stirred at RT for 1 h. Celite and water were added, theheterogenous mixture was vigorously stirred for 15 min, filtered and thefilter cake was washed with AcOEt. The filtrate was washed with a 2Maqueous Na₂CO₃ solution and the organic phase was dried over Na₂SO₄,filtered and evaporated to dryness. The resulting crude material waspurified by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, DCM/[DCM/MeOH 9:1] 95:5→2:8) to yield the titlecompound (162 mg, 0.245 mmol, 86%) as a yellow foam. TLC: R_(F)=0.31(DCM/MeOH 95:5); HPLC: ^(A)t_(Ret)=2.20 min; LC-MS: m/z 662.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆): 0.84-0.95 (2t, 3H, mixture of diastereoisomers),0.98-1.28 (m, 7H), 1.32-1.44 (m, 9H), 1.45-1.72 (m, 3H), 1.74-1.85 (m,1H), 1.89-2.04 (m, 1H), 2.24-2.37 (m, 1H), 2.57-2.80 (m, 2H), 3.60 (d,J=19.6, 1H), 3.68-3.92 (m, 7H), 4.18-4.31 (m, 1H), 6.07-6.14 (m, 1H),6.85 (s, 1H), 7.05-7.14 (m, 3H), 7.27-7.40 (m, 6H).

Example 62N-(1-{4-[7-((R)-sec-Butoxyl-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-piperidin-4-yl-acetamide

To a solution of Intermediate 61.1 (20 mg, 0.030 mmol) in DCM (0.5 ml)were successively added acetyl chloride (0.003 ml, 0.045 mmol) and Et₃N(0.013 ml, 0.090 mmol) at RT. The reaction mixture was stirred at RT for1 h then diluted with DCM and washed with water. The organic phase wasdried over Na₂SO₄, filtered and evaporated to dryness. The resultingresidue was dissolved in DCM (0.5 ml) then TFA (0.023 ml, 0.300 mmol)was added at RT. The reaction mixture was stirred at RT for 30 min thenevaporated to dryness. The resulting crude material was purified byreverse phase prep-HPLC (Waters system) to yield the title compound (TFAsalt, 11.6 mg, 0.016 mmol, 54%) as a colorless solid. HPLC:^(A)t_(Ret)=1.93 min; LC-MS: m/z 604.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.85-0.96 (m, 3H), 1.12-1.24 (m, 4H), 1.49-1.68 (m, 5H),1.68-1.78 (m, 1H), 2.78-3.02 (m, 4H), 3.13-3.22 (m, 1H), 3.25-3.33 (m,1H), 3.33-3.46 (m, 1H), 3.62 (d, J=19.7, 1H), 3.78 (s, 3H), 3.81-3.90(m, 1H), 4.15-4.26 (m, 1H), 4.93-5.02 (m, 1H), 6.02 (br. s., 1H), 6.84(s, 1H), 6.86-6.89 (m, 1H), 7.12-7.17 (m, 2H), 7.19-7.24 (m, 2H),7.25-7.34 (m, 4H).

Example 637-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[1-(methyl-piperidin-4-yl-amino)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 61.1 (25 mg, 0.038 mmol) in DCM (0.5 ml)were successively added AcOH (0.006 ml, 0.113 mmol), formaldehyde (37%in water, 0.008 ml, 0.113 mmol) and NaBH(OAc)₃ (24.0 mg, 0.113 mmol) atRT. The reaction mixture was stirred at RT for 1 h then diluted with DCMand washed with water. The organic phase was dried over Na₂SO₄, filteredand evaporated to dryness. The resulting yellow foam was dissolved inDCM (0.5 ml) and TFA (0.059 ml, 0.760 mmol) was added at RT. Thereaction mixture was stirred for 20 min then evaporated to dryness. Theresulting crude material was purified by reverse phase prep-HPLC (Waterssystem) to yield the title compound (TFA salt, 22 mg, 0.038 mmol,quant.) as a colorless solid. HPLC: ^(A)t_(Ret)=1.66 min; LC-MS: m/z576.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.85-0.96 (m, 3H), 1.12-1.30(m, 4H), 1.47-1.69 (m, 5H), 1.71-1.83 (m, 1H), 1.85-1.98 (m, 1H),2.04-2.18 (m, 1H), 2.24-2.36 (m, 1H), 2.36-2.46 (m, 2H), 2.60-2.71 (m,2H), 2.71-2.86 (m, 1H), 2.88-3.06 (m, 1H), 3.06-3.17 (m, 1H), 3.64 (d,J=20.1, 1H), 3.74 (s, 3H), 3.83-3.98 (m, 1H), 4.19-4.32 (m, 1H),4.61-4.87 (m, 1H), 6.12-6.23 (m, 1H), 6.88 (s, 1H), 7.03-7.13 (m, 1H),7.28-7.42 (m, 6H), 7.51-7.63 (m, 2H).

Example 647-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-{1-[(cis-4-dimethylamino-cyclohexyl)-methyl-amino]-ethyl}-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (TFA salt, 17.4 mg, 0.024 mmol, 54%) was obtained asa colorless solid by methylation of Intermediate 64.2 (TFA salt, 30 mg,0.043 mmol) with formaldehyde (37% in water, 0.013 ml, 0.17 mmol)analogously to Example 63. Purification of the crude material wasperformed by reverse phase prep-HPLC (Waters system). HPLC:^(A)t_(Ret)=1.71 min; LC-MS: m/z 618.5 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):0.87-1.01 (m, 3H, mixture of diastereoisomers), 1.12-1.27 (m, 3H,mixture of diastereoisomers), 1.46-2.44 (m, 13H), 2.57-2.73 (m, 1H),2.86-2.94 (m, 1H), 2.96 (s, 6H), 3.80 (d, J=20.1, 1H), 3.87 (s, 3H),4.08 (d, J=20.5, 1H), 4.19-4.28 (m, 1H), 4.68-4.82 (m, 1H), 6.05-6.10(m, 1H), 6.77-6.82 (m, 1H), 6.90 (s, 1H), 7.19-7.36 (m, 6H), 7.51-7.59(m, 2H).

Intermediate 64.1:[4-(1-{-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethylamino)-cis-cyclohexyl]-carbamicacid tert-butyl ester

The title compound (137 mg, 0.20 mmol, 97%) was obtained as a yellowresin from Intermediate 55.2 (100 mg, 0.21 mmol) and(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (135 mg, 0.63 mmol)analogously to Intermediate 61.1. Purification of the crude material wasperformed by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, [heptane/DCM 1:1]/TBME containing 5% of 7M NH₃in MeOH 95:5→100% TBME containing 5% of 7M NH₃ in MeOH). TLC: R_(F)=0.16(heptane/DCM/TBME containing 5% of 7M NH₃ in MeOH 1:1:2); HPLC:^(A)t_(Ret)=2.20 min; LC-MS: m/z 676.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.82-0.92 (m, 3H), 1.13-1.22 (m, 3H), 1.31-1.70 (m, 22H),2.28-2.37 (m, 1H), 3.22-3.31 (m, 1H), 3.60 (d, J=19.8, 1H), 3.71-3.80(m, 4H), 3.85 (dd, J=19.7, 3.3, 1H), 4.19-4.31 (m, 1H), 6.07-6.12 (m,1H), 6.55-6.62 (m, 1H), 6.86 (s, 1H), 7.06-7.13 (m, 3H), 7.27-7.32 (m,2H), 7.33-7.40 (m, 4H).

Intermediate 64.2:2-{4-[1-(cis-4-Amino-cyclohexylamino)-ethyl]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (TFA salt, 50 mg, 0.072 mmol, 49%) was obtained as acolorless solid by cleavage of the Boc protection of Intermediate 64.1(100 mg, 0.15 mmol) analogously to Example 61. Purification of the crudematerial was performed by reverse phase prep-HPLC (Waters system). HPLC:^(A)t_(Ret)=1.68 min; LC-MS: m/z 576.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):0.89-1.00 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.14-1.25 (2d,J=6.1, 3H, mixture of diastereoisomers), 1.48-1.75 (m, 5H), 1.76-2.06(m, 8H), 2.98-3.09 (m, 1H), 3.38-3.47 (m, 1H), 3.79 (d, J=20.5, 1H),3.86 (s, 3H), 4.07 (d, J=20.5, 1H), 4.17-4.29 (m, 1H), 4.55-4.64 (m,1H), 6.06 (br. s., 1H), 6.77-6.81 (m, 1H), 6.90 (s, 1H), 7.19-7.25 (m,2H), 7.26-7.34 (m, 4H), 7.49-7.55 (m, 2H).

Example 65N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-(cis-4-dimethylamino-cyclohexyl)-acetamide

To a solution of Intermediate 64.1 (35 mg, 0.052 mmol) in DCM (0.5 ml)were successively added acetyl chloride (0.006 ml, 0.078 mmol) and Et₃N(0.022 ml, 0.155 mmol) at RT. The reaction mixture was stirred at RT for1 h, diluted with DCM and washed with water. The organic layer was driedover Na₂SO₄, filtered and evaporated to dryness. The resulting yellowfoam was dissolved in DCM (0.5 ml) and TFA (0.08 ml, 1.0 mmol) wasadded. The mixture was stirred at RT for 1 h then evaporated to dryness.The resulting brown resin was dissolved in DCM (0.7 ml) and AcOH (0.009ml, 0.155 mmol), formaldehyde 37% in water (0.012 ml, 0.155 mmol) andNaBH(OAc)₃ (32.9 mg, 0.155 mmol) were successively added at RT. Thereaction mixture was stirred at RT for 1 h, diluted with DCM and washedwith water. The organic layer was dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byreverse phase prep-HPLC (Waters system) to yield the title compound (TFAsalt, 16.8 mg, 0.022 mmol, 42%) as a colorless solid. HPLC:^(A)t_(Ret)=1.99 min; LC-MS: m/z 646.5 [M+H]⁺.

Example 662-{4-[1-(trans-4-Amino-cyclohexylamino)-ethyl]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

A solution of Intermediate 66.1 (40 mg, 0.056 mmol) in EtOH (1 ml) wasevacuated under vacuum and back filled with argon (2×). Ammonium formate(5.3 mg, 0.084 mmol) and Pd/C (3.0 mg, 0.003 mmol) were added at RT andthe suspension was vigorously stirred for 1 h. The reaction mixture wasfiltered over a Celite pad, the catalyst was washed with DCM and thefiltrate evaporated to dryness. The resulting crude material waspurified by reverse phase prep-HPLC (Waters system) to yield the titlecompound (TFA salt, 12.6 mg, 0.018 mmol, 32%) as a colorless solid.HPLC: ^(A)t_(Ret)=1.73 min; LC-MS: m/z 576.4 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD): 0.88-1.01 (2t, J=7.5, 3H, mixture of diastereoisomers),1.13-1.27 (2d, J=6.1, 3H, mixture of diastereoisomers), 1.33-1.78 (m,9H), 2.09-2.23 (m, 3H), 2.28-2.38 (m, 1H), 2.90-3.03 (m, 1H), 3.07-3.18(m, 1H), 3.79 (d, J=20.3, 1H), 3.86 (s, 3H), 4.09 (d, J=20.3, 1H),4.18-4.31 (m, 1H), 4.52-4.63 (m, 1H), 6.05 (s, 1H), 6.77-6.83 (m, 1H),6.90 (s, 1H), 7.19-7.26 (m, 2H), 7.26-7.35 (m, 4H), 7.48-7.55 (m, 2H).

Intermediate 66.1:[4-(1-{-4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethylamino)-trans-cyclohexyl]-carbamicacid benzyl ester

The title compound (232 mg, 0.29 mmol, 70%) was obtained as a yellowresin from Intermediate 55.2 (200 mg, 0.42 mmol) andtrans-(4-amino-cyclohexyl)-carbamic acid benzyl ester (312 mg, 1.26mmol) analogously to Intermediate 61.1. Purification of the crudematerial was performed by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, [heptane/DCM 1:1]/TBMEcontaining 5% of 7M NH₃ in MeOH 95:5→100% TBME containing 5% of 7M NH₃in MeOH). TLC: R_(F)=0.10 (heptane/DCM/TBME containing 5% of 7M NH₃ inMeOH 1:1:2); HPLC: ^(A)t_(Ret)=2.24 min; LC-MS: m/z 710.4 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): 0.80-0.93 (m, 3H), 1.09-1.20 (m, 3H),1.43-2.10 (m, 12H), 3.12-3.25 (m, 1H), 3.60 (d, J=19.6, 1H), 3.74 (s,3H), 3.78-3.90 (m, 2H), 4.17-4.32 (m, 1H), 4.95-5.01 (m, 2H), 6.10 (br.s., 1H), 6.86 (s, 1H), 7.03-7.14 (m, 4H), 7.25-7.41 (m, 11H).

Example 677-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-(4-dimethylamino-piperidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 67.2 (20 mg, 0.030 mmol) in DCM (0.5 ml)were successively added AcOH (0.005 ml, 0.089 mmol), formaldehyde (37%in water, 0.007 ml, 0.089 mmol) and NaBH(OAc)₃ (18.81 mg, 0.089 mmol) atRT. The reaction mixture was stirred at RT for 1 h then diluted with DCMand washed with water. The organic phase was dried over Na₂SO₄, filteredand evaporated to dryness. The resulting crude material was purified byreverse phase prep-HPLC (Waters system) to yield the title compound (TFAsalt, 7.5 mg, 0.011 mmol, 36%) as a colorless solid. HPLC:^(A)t_(Ret)=1.70 min; LC-MS: m/z 590.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):0.89-1.01 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.14-1.26 (2d,J=6.1, 3H, mixture of diastereoisomers), 1.49-1.74 (m, 2H), 1.74-1.80(m, 3H), 1.96-2.17 (m, 2H), 2.28-2.45 (m, 2H), 2.84-3.07 (m, 2H), 2.91(s, 6H), 3.38-3.48 (m, 1H), 3.51-3.61 (m, 1H), 3.79 (d, J=20.3, 1H),3.83-3.95 (m, 1H), 3.86 (s, 3H), 4.07 (d, J=20.3, 1H), 4.18-4.31 (m,1H), 4.48-4.59 (m, 1H), 6.06 (s, 1H), 6.79-6.85 (m, 1H), 6.90 (s, 1H),7.19-7.26 (m, 2H), 7.27-7.36 (m, 4H), 7.50-7.58 (m, 2H).

Intermediate 67.1:[1-(1-{-4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-piperidin-4-yl]-carbamicacid tert-butyl ester

The title compound (230 mg, 0.35 mmol, 83%) was obtained as a yellowresin from Intermediate 55.2 (200 mg, 0.42 mmol) andpiperidin-4-yl-carbamic acid tert-butyl ester (251 mg, 1.26 mmol)analogously to Intermediate 61.1. Purification of the crude material wasperformed by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, [heptane/DCM 1:1]/TBME containing 5% of 7M NH₃in MeOH 95:5→100% TBME containing 5% of 7M NH₃ in MeOH). TLC: R_(F)=0.29(heptane/DCM/TBME containing 5% of 7M NH₃ in MeOH 1:1:2); HPLC:^(A)t_(Ret)=2.15 min; LC-MS: m/z 662.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.83-0.96 (m, 3H), 1.13-1.22 (m, 3H), 1.33-1.40 (m, 9H),1.45-1.96 (m, 8H), 2.26-2.42 (m, 1H), 2.57-2.67 (m, 1H), 2.81-3.00 (m,2H), 3.06-3.20 (m, 1H), 3.35-3.43 (m, 1H), 3.60 (d, J=19.8, 1H), 3.73(s, 3H), 3.84 (dd, J=19.7, 3.8, 1H), 4.18-4.34 (m, 1H), 5.70-5.82 (m,1H), 6.06-6.15 (m, 1H), 6.67-6.78 (m, 1H), 6.86 (s, 1H), 7.06-7.17 (m,3H), 7.20-7.29 (m, 2H), 7.31-7.42 (m, 4H).

Intermediate 67.2:2-{4-[1-(4-Amino-piperidin-1-yl)-ethyl]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (TFA salt, 25.3 mg, 0.037 mmol, 59%) was obtained asa colorless solid from Intermediate 67.1 (41.7 mg, 0.063 mmol) bytreatment with TFA analogously to Example 61. Purification of the crudematerial was performed by reverse phase prep-HPLC (Waters system). HPLC:^(A)t_(Ret)=1.70 min; LC-MS: m/z 562.6 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):0.88-1.01 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.13-1.26 (2d,J=6.1, 3H, mixture of diastereoisomers), 1.51-1.81 (m, 5H), 1.83-2.07(m, 2H), 2.16-2.34 (m, 2H), 2.80-3.12 (m, 2H), 3.34-3.43 (m, 1H),3.44-3.53 (m, 1H), 3.79 (d, J=20.3, 1H), 3.79-3.89 (m, 1H), 3.86 (s,3H), 4.08 (d, J=20.1, 1H), 4.18-4.30 (m, 1H), 4.43-4.59 (m, 1H), 6.06(s, 1H), 6.77-6.84 (m, 1H), 6.90 (s, 1H), 7.19-7.26 (m, 2H), 7.26-7.35(m, 4H), 7.48-7.57 (m, 2H).

Example 687-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-{1-[4-(isopropyl-methyl-amino)-piperidin-1-yl]-ethyl}-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (TFA salt, 15.3 mg, 0.021 mmol, 43%) was obtainedfrom Intermediate 67.2 (27 mg, 0.048 mmol) after two consecutivereductive amination with acetone and formaldehyde respectively,analogously to Example 53. Purification of the crude material wasperformed by reverse phase prep-HPLC (Waters system). HPLC:^(A)t_(Ret)=1.71 min; LC-MS: m/z 618.6 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):0.89-1.01 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.15-1.26 (2d,J=6.1, 3H, mixture of diastereoisomers), 1.29-1.43 (m, 6H), 1.49-1.80(m, 5H), 1.95-2.20 (m, 2H), 2.23-2.49 (m, 2H), 2.80-3.06 (m, 2H),3.22-3.37 (m, 3H), 3.45-3.65 (m, 2H), 3.78 (d, J=20.5, 1H), 3.78-3.88(m, 1H), 3.86 (s, 3H), 4.07 (d, J=20.1, 1H), 4.20-4.30 (m, 1H),4.39-4.55 (m, 1H), 6.06 (s, 1H), 6.79-6.85 (m, 1H), 6.90 (s, 1H),7.20-7.26 (m, 2H), 7.27-7.36 (m, 4H), 7.49-7.58 (m, 2H).

Example 69N-[1-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl]-piperidin-4-yl]-acetamide

To a solution of Intermediate 67.2 (24 mg, 0.043 mmol) in MeCN (0.5 ml)were successively added Et₃N (0.018 ml, 0.13 mmol) and acetyl chloride(0.005 ml, 0.064 mmol) at RT. The reaction mixture was stirred at RT for1 h then directly subjected to purification by reverse phase prep-HPLC(Waters system) to yield the title compound (TFA salt, 3.2 mg, 0.004mmol, 10%) as a colorless solid. HPLC: ^(A)t_(Ret)=1.88 min; LC-MS: m/z604.5 [M+H]⁺.

Example 702-{4-[1-(4-Acetyl-piperazin-1-yl)-ethyl]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 70.1 (TFA salt, 15.4 mg, 0.023 mmol) inMeCN (0.5 ml) were successively added Et₃N (0.013 ml, 0.093 mmol) andacetyl chloride (0.003 ml, 0.035 mmol) at RT. The reaction mixture wasstirred at RT for 1 h then directly subjected to purification by reversephase prep-HPLC (Waters system) to yield the title compound (TFA salt,7.6 mg, 0.011 mmol, 46%) as a colorless solid. HPLC: ^(A)t_(Ret)=1.90min; LC-MS: m/z 590.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 0.88-1.02 (2t,J=7.5, 3H, mixture of diastereoisomers), 1.12-1.27 (2d, J=6.1, 3H,mixture of diastereoisomers), 1.48-1.74 (m, 2H), 1.74-1.83 (m, 3H), 2.13(s, 3H), 2.81-3.40 (m, 8H), 3.79 (d, J=20.3, 1H), 3.86 (s, 3H), 4.07 (d,J=20.3, 1H), 4.18-4.29 (m, 1H), 4.46-4.56 (m, 1H), 6.06 (s, 1H),6.78-6.83 (m, 1H), 6.90 (s, 1H), 7.19-7.26 (m, 2H), 7.28-7.35 (m, 4H),7.48-7.54 (m, 2H).

Intermediate 70.1:7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(1-piperazin-1-yl-ethyl)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

The title compound (TFA salt, 18.9 mg, 0.029 mmol, 45%) was obtained asa colorless solid from Intermediate 55.2 (30 mg, 0.063 mmol) andpiperazine-1-carboxylic acid tert-butyl ester (35.1 mg, 0.188 mmol)analogously to Example 61. Purification of the crude material wasperformed by reverse phase prep-HPLC (Waters system). HPLC:^(A)t_(Ret)=1.71 min; LC-MS: m/z 548.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD):0.87-1.01 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.13-1.27 (2d,J=6.1, 3H, mixture of diastereoisomers), 1.46-1.54 (m, 3H), 1.54-1.78(m, 2H), 2.79-3.06 (m, 4H), 3.24-3.38 (m, 4H), 3.76 (d, J=20.3, 1H),3.82-3.92 (m, 4H), 4.05 (d, J=20.1, 1H), 4.19-4.30 (m, 1H), 6.01 (s,1H), 6.80-6.85 (m, 1H), 6.90 (s, 1H), 7.15-7.25 (m, 4H), 7.28-7.34 (m,2H), 7.39-7.46 (m, 2H).

Example 71

Compounds 71aa to 71ca were obtained from Intermediate 55.2 (oranalogues prepared similarly) or Intermediate 58.1 (or analoguesprepared similarly) analogously to Example 55 to 70.

# Structure Name/HPLC/MS 71aa

7-((R)-sec-Butoxy)-1-(4-chloro-pheny1)-2-[4-(1-dimethylamino-ethylyphenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.97; LC-MS: m/z507.3 [M + H]⁺. 71ab

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-(4-hydroxy-piperidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.88;LC-MS: m/z 563.3 [M + H]⁺. 71ac

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-(2-dimethylamino-ethylamino)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.72; LC-MS: m/z 550.5 [M + H]⁺. 71ad

2-{4-[1-(1-Acetyl-piperidin-4-ylamino)-ethyl]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.88; LC-MS: m/z 604.7 [M + H]⁺. 71ae

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-((R)-3-hydroxy-pyrrolidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.88; LC-MS: m/z 549.5 [M + H]⁺. 71af

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-((S)-3-hydroxy-pyrrolidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.88; LC-MS: m/z 549.4 [M + H]⁺. 71ag

1-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-piperidine-4- carboxylic acid amide.HPLC: ^(A)t_(Ret) = 1.87; LC-MS: m/z 590.4 [M + H]⁺. 71ah

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-((S)-3-hydroxy-piperidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.90; LC-MS: m/z 563.4 [M + H]⁺. 71ai

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-((R)-3-hydroxy-piperidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.91; LC-MS: m/z 563.3 [M + H]⁺. 71aj

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(1-thiomorpholin-4-yl-ethyl)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.99;LC-MS: m/z 565.3 [M + H]⁺. 71ak

N-(1-{4-[7-((R)-secButoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-isobutyl- acetamide. HPLC:^(A)t_(Ret) = 2.83; LC-MS: m/z 577.3 [M + H]⁺. 71al

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-propyl- acetamide. HPLC: ^(A)t_(Ret)= 2.71; LC-MS: m/z 563.3 [M + H]⁺. 71am

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-isopropyl- acetamide. HPLC:^(A)t_(Ret) = 2.71; LC-MS: m/z 563.4 [M + H]⁺. 71an

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-cyclopropyl- acetamide. HPLC:^(A)t_(Ret) 2.69; LC-MS: m/z 561.4 [M + H]⁺. 71ao

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N- cyclohexylmethyl-acetamide. HPLC:^(A)t_(Ret) = 3.13; LC-MS: m/z 617.5 [M + H]⁺. 71ap

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-cyclopentyl- acetamide. HPLC:^(A)t_(Ret) = 2.90; LC-MS: m/z 589.4 [M + H]⁺. 71aq

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-cyclohexyl- acetamide. HPLC:^(A)t_(Ret) = 3.02; LC-MS: m/z 603.3 [M + H]⁺. 71ar

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl0-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N- cyclopropylmethyl-acetamide. HPLC:^(A)t_(Ret) = 2.75; LC-MS: m/z 575.3 [M + H]⁺. 71as

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N- cyclopentylmethyl-acetamide. HPLC:^(A)t_(Ret) = 3.03; LC-MS: m/z 603.6 [M + H]⁺. 71at

N-Benzyl-N-(1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-acetamide. HPLC: ^(A)t_(Ret) = 2.87;LC-MS: m/z 611.5 [M + H]⁺. 71au

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-cyclobutyl- acetamide. HPLC:^(A)t_(Ret) = 2.81; LC-MS: m/z 575.3 [M + H]⁺. 71av

1-Methyl-piperidine-4-carboxylic acid (1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethylamide. HPLC: ^(A)t_(Ret) = 2.00; LC-MS: m/z632.7 [M + H]⁺. 71aw

1-Methyl-piperidine-3-carboxylic acid (1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethylamide. HPLC: ^(A)t_(Ret) = 2.05; LC-MS: m/z632.7 [M + H]⁺. 71ax

(1S,3R)-3-Amino-cyclopentanecarboxylic acid(1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethylamide. HPLC:^(A)t_(Ret) = 2.08; LC-MS: m/z618.7 [M + H]⁺. 71ay

(1R,3R)-3-Amino-cyclopentanecarboxylic acid(1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethylamide. HPLC: ^(A)t_(Ret) = 2.02;LC-MS: m/z 618.7 [M + H]⁺. 71az

Pyrrolidine-3-carboxylic acid (1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}- ethyl)-ethylamide. HPLC:^(A)t_(Ret) = 2.01; LC-MS: m/z 604.6 [M + H]⁺. 71ba

Cis-4-Amino-cyclohexanecarboxylic acid (1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethylamide. HPLC: ^(A)t_(Ret) = 2.08; LC-MS: m/z632.5 [M + H]⁺. 71bb

Trans-4-Amino-cyclohexanecarboxylic acid(1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethylamide. HPLC: ^(A)t_(Ret) = 2.03; LC-MS: m/z632.5 [M + H]⁺.  71bc⁽¹⁾

Trans-4-Dimethylamino-cyclohexane- carboxylic acid(1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)- ethylamide. HPLC: ^(A)t_(Ret) =2.07; LC-MS: m/z 660.7 [M + H]⁺. 71bd

(1R,3R)-3-Dimethylamino- cyclopentanecarboxylic acid (1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}- ethyl)-ethylamide. HPLC:^(A)t_(Ret) = 2.05; LC-MS: m/z 645.3 [M + H]⁺. 71be

1-Methyl-pyrrolidine-3-carboxylic acid (1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethylamide. HPLC: ^(A)t_(Ret) = 2.04; LC-MS: m/z618.5[M + H]⁺. 71bf

Cis-4-Dimethylamino-cyclohexanecarboxylic acid(1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-ethylamide. HPLC: ^(A)t_(Ret) = 2.12;LC-MS: m/z 660.7 [M + H]⁺. 71bg

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[1-((S)-piperidin-3-ylamino)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3- one. HPLC: ^(A)t_(Ret) =1.70; LC-MS: m/z 562.2 [M + H]⁺. 71bh

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[1-((R)-piperidin-3-ylamino)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3- one. HPLC: ^(A)t_(Ret) =1.71; LC-MS: m/z 562.3 [M + H]⁺. 71bi

N-((S)-1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-(R)- piperidin-3-yl-acetamide. HPLC:^(A)t_(Ret) = 1.93; LC-MS: m/z 604.4 [M + H]⁺. 71bj

N-((R)-1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-(R)- piperidin-3-yl-acetamide. HPLC:^(A)t_(Ret) = 2.02; LC-MS: m/z 604.3 [M + H]⁺. 71bk

N-((S)-1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-(S)- piperidin-3-yl-acetamide. HPLC:^(A)t_(Ret) 2.02; LC-MS: m/z 604.3 [M + H]⁺. 71bl

N-((R)-1 -{4-[7-((R)-sec-Butoxy)-1 -(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-(S)- piperidin-3-yl-acetamide. HPLC:^(A)t_(Ret) = 1 -92; LC-MS: m/z 604.3 [M + H]⁺. 71bm

N-(2-Amino-ethyl)-N-(1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}- ethyl)-acetamide. HPLC:^(A)t_(Ret) = 1.92; LC-MS: m/z 564.5 [M + H]⁺. 71bn

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-(2- dimethylamino-ethyl)-acetamide.HPLC: ^(A)t_(Ret) = 1.94; LC-MS: m/z 592.4 [M + H]⁺. 71bo

N-(3-Amino-propyl)-N-(1-{4-[7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}- ethyl)-acetamide. HPLC:^(A)t_(Ret) = 1.93; LC-MS: m/z 578.4 [M + H]⁺. 71bp

N-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-(3- dimethylamino-propyl)-acetamide.HPLC: ^(A)t_(Ret) = 1.96; LC-MS: m/z 606.4 [M + H]⁺. 71bq

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-(ethyl-piperidin-4-yl-amino)-ethyl)-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.68;LC-MS: m/z 590.5 [M + H]⁺. 71br

2-{4-[1-((S)-3-Amino-piperidin-1-yl)-ethyl]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.72; LC-MS: m/z 562.3 [M + H]⁺. 71bs

2-{4-[1-((R)-3-Amino-pyrrolidin-1-yl)-ethyl]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.73; LC-MS: m/z 548.3 [M + H]⁺. 71bt

2- {4-[1-((S)-3-Amino-pyrrolidin-1-yl)-ethyl]-phenyl}-7-((R)-sec-butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.71; LC-MS: m/z 548.3 [M + H]⁺. 71bu

N-[(S)-1-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-piperidin-3- yl]-acetamide. HPLC:^(A)t_(Ret) = 1.90; LC-MS: m/z 604.3 [M + H]⁺. 71bv

N-[(R)-1-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-pyrrolidin- 3- yl]-acetamide. HPLC:^(A)t_(Ret) = 1.88; LC-MS: m/z 590.3 [M + H]⁺. 71bw

N-[(S)-1-(1-{4-[7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-pyrrolidin- 3-yl]-acetamide. HPLC:^(A)t_(Ret) = 1.88; LC-MS: m/z 590.3 [M + H]⁺. 71bx

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-((S)-3-dimethylamino-piperidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.74; LC-MS: m/z 590.4 [M + H]⁺. 71by

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-((S)-3-dimethylamino-pyrrolidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.77; LC-MS: m/z 576.4 [M + H]⁺. 71bz

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-((R)-3-dimethylamino-pyrrolidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =1.72; LC-MS: m/z 576.5 [M + H]⁺. 71ca

7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-(4-diethylamino-piperidin-1-yl)-ethyl]-phenyl}-6-methoxy-1(4-dihydro-2H- isoquinolin-3-one. HPLC: ^(A)t_(Ret) =170; LC-MS: m/z 618.5 [M + H]⁺. ⁽¹⁾The title compound (TFA salt, 7.9 mg,0.01 mmol, 63%) was obtained as a colorless solid from Example before(TFA salt, 12 mg, 0.016 mmol) analogously to Example 67. Purification ofthe crude material was performed by reverse phase prep-HPLC (Waterssystem).

Example 727-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-{4-[1-(3-oxo-morpholin-4-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 72.1 (53 mg, 0.10 mmol) and Et₃N (0.042ml, 0.30 mmol) in DCM (1 ml) was added chloroacetyl chloride (0.020 ml,0.25 mmol) at RT. The reaction mixture was stirred at RT for 1 h thenevaporated to dryness. The resulting residue was dissolved in EtOH (0.5ml) and NaOH (35% in water, 0.025 ml, 0.22 mmol) was added at RT. Thesuspension was well stirred for 2 h then diluted with DCM and washedwith water. The organic phase was dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byreverse phase prep-HPLC (Waters system) to yield the title compound(18.9 mg, 0.034 mmol, 33%) as a light yellow solid. HPLC:^(A)t_(Ret)=2.45 min; LC-MS: m/z 563.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.83-0.96 (m, 3H), 1.12-1.25 (2d, J=6.1, 3H, mixture ofdiastereoisomers), 1.40-1.48 (m, 3H), 1.48-1.72 (m, 2H), 2.75-2.86 (m,1H), 3.23-3.36 (m, 1H), 3.61 (d, J=19.8, 1H), 3.68-3.93 (m, 5H), 4.10(s, 2H), 4.18-4.31 (m, 1H), 5.76 (q, J=7.3, 1H), 6.11 (d, J=3.2, 1H),6.86 (s, 1H), 7.06-7.12 (m, 1H), 7.15-7.21 (m, 2H), 7.24-7.30 (m, 2H),7.33-7.39 (m, 4H).

Intermediate 72.1:7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[1-(2-hydroxy-ethylamino)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (139 mg, 0.27 mmol, 63%) was obtained as a yellowsolid from Intermediate 55.2 (200 mg, 0.42 mmol) and ethanolamine (0.076ml, 1.26 mmol) analogously to Intermediate 61.1. Purification of thecrude material was performed by Combi-Flash Companion™ (Isco Inc.)column chromatography (SiO₂; gradient elution, DCM/MeOH 99.5:0.5→9:1).TLC: R_(F)=0.26 (DCM/MeOH 9:1); HPLC: ^(A)t_(Ret)=1.88 min; LC-MS: m/z523.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.82-0.97 (m, 3H), 1.11-1.25(2d, J=6.1, 3H, mixture of diastereoisomers), 1.45-1.72 (m, 5H),2.59-2.75 (m, 1H), 2.81-2.97 (m, 1H), 3.53-3.95 (m, 7H), 4.18-4.32 (m,1H), 4.33-4.46 (m, 1H), 6.16 (br. s., 1H), 6.87 (s, 1H), 7.10 (d, J=6.6,1H), 7.23-7.42 (m, 6H), 7.44-7.55 (m, 2H), 8.73-8.91 (m, 1H), 8.94-9.10(m, 1H).

Example 73a(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(trans-4-dimethylamino-cyclohexylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-oneand Example 73b(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(trans-4-dimethylamino-cyclohexylmethyl)-methyl-amino]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title examples were obtained by chiral separation of the racemicExample 54bj. The chiral chromatography was performed using a GilsonHPLC system with a Chiralpak AD 500×50 mm, 20 M column, eluting with 40%EtOH+0.1% diethylamine in n-heptane with a flow rate of 60-120 ml/min.

Example 73a: HPLC: HPLC: ^(A)t_(Ret)=1.97; LC-MS: m/z 604.6 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆): 0.86 (t, J=7.5, 3H), 0.94-1.06 (m, 2H), 1.18 (d,J=6.1, 3H), 1.22-1.34 (m, 2H), 1.43-1.67 (m, 3H), 1.71-1.80 (m, 2H),1.85-1.94 (m, 2H), 2.54 (br. s., 6H), 2.76-2.90 (m, 1H), 2.87 (s, 3H),3.11 (d, J=7.0, 2H), 3.56 (d, J=19.8, 1H), 3.72 (s, 3H), 3.88 (d,J=19.8, 1H), 4.17-4.24 (m, 1H), 5.94 (s, 1H), 6.52-6.59 (m, 2H), 6.82(s, 1H), 6.86-6.91 (m, 2H), 7.01 (s, 1H), 7.34 (s, 4H).

Example 73b: HPLC: ^(A)t_(Ret)=1.98; LC-MS: m/z 604.6 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆): 0.90 (t, J=7.5, 3H), 0.97-1.07 (m, 2H), 1.11 (d,J=6.0, 3H), 1.30-1.42 (m, 2H), 1.49-1.69 (m, 3H), 1.73-1.82 (m, 2H),1.91-1.98 (m, 2H), 2.66-2.72 (2s, 6H), 2.87 (s, 3H), 2.89-2.96 (m, 1H),3.12 (d, J=7.0, 2H), 3.55 (d, J=19.8, 1H), 3.72 (s, 3H), 3.88 (d,J=19.8, 1H), 4.21-4.29 (m, 1H), 5.93 (s, 1H), 6.53-6.60 (m, 2H), 6.82(s, 1H), 6.87-6.92 (m, 2H), 7.02 (s, 1H), 7.34 (s, 4H).

Example 74

Compounds 74aa to 74bb were obtained analogously to Example 73 by chiralcolumn chromatography performed on the corresponding racemic mixture.

# Structure Name/HPLC/MS 74aa

(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(B)t_(Ret) = 2.78; API-MS: m/z 466.2 [M + H]⁺. 74ab

(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(B)t_(Ret) = 2.78; API-MS: m/z 466.2 [M + H]⁺. 74ac

(S)-7-((S)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(B)t_(Ret) = 2.78; API-MS: m/z 466.2 [M + H]⁺. 74ad

(R)-7-((S)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(B)t_(Ret) = 2.78; API-MS: m/z 466.2 [M + H]⁺. 74ae

(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.03 min; API-MS: m/z 480.6 [M + H]⁺. 74af

(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.03 min; API-MS: m/z 480.6 [M + H]⁺. 74ag

4-[(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-N-ethyl-N-methyl-benzamide. HPLC: ^(A)t_(Ret) = 2.47; LC-MS: m/z 521.4[M + H]⁺. 74ah

4-[(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-N-ethyl-N-methyl-benzamide. HPLC: ^(A)t_(Ret) = 2.46; LC-MS: m/z 521.3[M + H]⁺. 74ai

(S)-1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin- 3-one. HPLC:^(A)t_(Ret) = 1.87; LC-MS: m/z 465.3 [M + H]⁺. 74aj

(R)-1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin- 3-one. HPLC:^(A)t_(Ret) = 1.87; LC-MS: m/z 465.3 [M + H]⁺. 74ak

(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(cyclopropylmethyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.09;LC-MS: m/z 519.4 [M + H]⁺. 74al

(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-[4-(cyclopropylmethyl-methyl-amino)-phenyl]-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.09;LC-MS: m/z 519.4 [M + H]⁺. 74am

(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(2-oxo-azetidin-1-yl)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.49; LC-MS: m/z 505.4[M + H]⁺. 74an

(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(2-oxo-azetidin-1-yl)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.49; LC-MS: m/z 505.5[M + H]⁺. 74ao

(S)-1-(4-Chloro-phenyl)-7-cyclobutoxy-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.94; LC-MS: m/z 477.3 [M + H]⁺. 74ap

(R)-1-(4-Chloro-phenyl)-7-cyclobutoxy-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.94; LC-MS: m/z 477.3 [M + H]⁺. 74aq

(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.05;LC-MS: m/z 556.2 [M + H]⁺. 74ar

(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-[4-(methyl-pyridin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.06;LC-MS: m/z 556.2 [M + H]⁺. 74as

N-((S)-1-{4-[(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-ethyl-acetamide. HPLC: ^(A)t_(Ret) = 2.57; LC-MS:m/z 549.6 [M + H]⁺. 74at

N-((R)-1-{4-[(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-ethyl-acetamide. HPLC: ^(A)t_(Ret) = 2.57; LC-MS:m/z 549.4 [M + H]⁺. 74au

N-((S)-1-{4-[(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-ethyl-acetamide. HPLC: ^(A)t_(Ret) = 2.58; LC-MS:m/z 549.5 [M + H]⁺. 74av

N-((R)-1-{4-[(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-N-ethyl-acetamide. HPLC: ^(A)t_(Ret) = 2.58; LC-MS:m/z 549.6 [M + H]⁺. 74aw

N-{4-[({4-[(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}- propionamide. HPLC:^(A)t_(Ret) = 2.22; LC-MS: m/z 632.6 [M + H]⁺. 74ax

N-{4-[({4-[(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}- propionamide. HPLC:^(A)t_(Ret) = 2.22; LC-MS: m/z 632.7 [M + H]⁺. 74ay

(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(S)-1-(4-dimethylamino-piperidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.72;LC-MS: m/z 590.7 [M + H]⁺. 74az

(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(R)-1-(4-dimethylamino-piperidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.73;LC-MS: m/z 590.7 [M + H]⁺. 74ba

(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(S)-1-(4-dimethylamino-piperidin-1-yl)-ethyl)-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.70;LC-MS: m/z 590.7 [M + H]⁺. 74bb

(R)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-2-{4-[(R)-1-(4-dimethylamino-piperidin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1 72;LC-MS: m/z 590.7 [M + H]⁺.

Example 75(S)-1-(4-Chloro-phenyl)-2-{4-[(trans-4-dimethylamino-cyclohexylmethyl)-methyl-amino]-phenyl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

A sealable reaction flask was charged with Intermediate 75.6 (30 mg,0.087 mmol), CuI (3.3 mg, 0.017 mmol),(+/−)-trans-1,2-diaminocyclohexane (0.002 ml, 0.017 mmol) and K₃PO₄(36.8 mg, 0.17 mmol) then evacuated under vacuum and back-filled withargon (3×). A solution of Intermediate 75.8 (48.4 mg, 0.13 mmol) inanhydrous dioxane (0.5 ml) was added, the reaction flask was sealed andthe slurry was heated at 110° C. and stirred for 14 h. The reactionmixture was cooled to RT, diluted with DCM and washed with a 2M aqueousNa₂CO₃ solution. The organic phase was dried over Na₂SO₄, filtered andevaporated. The resulting crude material was purified by reverse phaseprep-HPLC (Waters system) to yield the title compound (TFA salt, 25 mg,0.036 mmol, 40%) as a brownish solid. HPLC: ^(A)t_(Ret)=1.83 min; LC-MS:m/z 590.7 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆). 0.96-1.10 (m, 2H), 1.19 (d,J=6.1, 3H), 1.24 (d, J=6.1, 3H), 1.30-1.46 (m, 2H), 1.59-1.71 (m, 1H),1.74-1.86 (m, 2H), 1.90-2.03 (m, 2H), 2.71 (2s, 6H), 2.89 (s, 3H),3.03-3.19 (m, 3H), 3.57 (d, J=19.8, 1H), 3.73 (s, 3H), 3.90 (d, J=19.8,1H), 4.39-4.51 (m, 1H), 5.94 (s, 1H), 6.54-6.63 (m, 2H), 6.84 (s, 1H),6.87-6.95 (m, 2H), 7.03 (s, 1H), 7.35 (s, 4H), 9.22-9.37 (m, 1H).

Intermediate 75.1: (4-Isopropoxy-3-methoxy-phenyl)-acetic acid ethylester

A mixture of ethyl (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester(11.22 g, 53.4 mmol) and K₂CO₃ (22.13 g, 160 mmol) in DMF (100 ml) washeated at 60° C. 2-Iodopropane (9.06 ml, 91 mmol) was added and themixture was vigorously stirred at 60° C. for 5 h. The reaction mixturewas cooled to RT, diluted with AcOEt and washed with water. The aqueousphase was separated and further extracted with AcOEt. The combinedorganic fractions were dried over Na₂SO₄, filtered and evaporated todryness. The resulting crude material was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,heptane/AcOEt 98:2→3:1) to yield the title compound (11.94 g, 47.3 mmol,89%) as a colorless oil. TLC: R_(F)=0.44 (heptane/AcOEt 7:3); HPLC:^(A)t_(Ret)=2.14 min; LC-MS: m/z 253.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃):1.28 (t, J=7.1, 3H), 1.38 (d, J=6.1, 6H), 3.56 (s, 2H), 3.87 (s, 3H),4.17 (q, J=7.1, 2H), 4.50 (h, J=6.1, 1H), 6.77-6.89 (m, 3H).

Intermediate 75.2: (2-Formyl-4-isopropoxy-5-methoxy-phenyl)-acetic acidethyl ester

To a solution of Intermediate 75.1 (11.94 g, 47.3 mmol) anddichloro-methoxy-methane (8.56 ml, 95 mmol) in DCM (350 ml) was slowlyadded SnCl₄ (1M solution in DCM, 95 ml, 95 mmol) over a 45 min period at0° C. (ice bath). After the addition, the reaction mixture was furtherstirred at 0° C. for 45 min then poured into water and extracted withDCM (2×). The organic phase was washed with a 2M aqueous Na₂CO₃solution, then dried over Na₂SO₄, filtered and evaporated to dryness.The resulting crude material was purified by Combi-Flash Companion™(Isco Inc.) column chromatography (SiO₂; gradient elution, heptane/AcOEt95:5→1:1) to yield the title compound (11.13 g, 39.7 mmol, 84%) as ayellow oil which crystallized on standing into an off-white solid. TLC:R_(F)=0.50 (heptane/AcOEt 1:1); HPLC: ^(A)t_(Ret)=1.93 min; LC-MS: m/z281.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 1.18 (t, J=7.1, 3H) 1.28 (d,J=6.1, 6H) 3.84 (s, 3H) 4.01 (s, 2H) 4.07 (q, J=7.1, 2H) 4.56-4.68 (m,1H) 7.03 (s, 1H) 7.45 (s, 1H) 9.93 (s, 1H).

Intermediate 75.3:(4-Isopropoxy-5-methoxy-2-{[(E)-(S)-2-methyl-propane-2-sulfinylimino]-methyl}-phenyl)-aceticacid ethyl ester

To a solution of Intermediate 75.2 (9.14 g, 32.6 mmol) and(S)-(−)-2-methyl-2-propanesulfinamide (5.93 g, 48.9 mmol) in DCM (200ml) was added Ti(OEt)₄ (27.3 ml, 130 mmol) at 0° C. (ice bath). Thereaction mixture was heated at reflux, stirred for 5 h then cooled to RTand quenched by the careful addition of water (14.7 ml). The resultingwhite precipitate was filtered through a Celite pad, the filter cake waswashed with DCM and the filtrate then evaporated to dryness. Theresulting crude material was purified by Combi-Flash Companion™ (IscoInc.) column chromatography (SiO₂; gradient elution, heptane/AcOEt95:5→1:1) to yield the title compound (11.07 g, 28.9 mmol, 89%) as ayellow oil. TLC: R_(F)=0.40 (heptane/AcOEt 1:1); HPLC: ^(A)t_(Ret)=2.35min; LC-MS: m/z 384.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 1.17 (t, J=7.1,3H) 1.15 (s, 9H) 1.27 (d, J=6.1, 6H) 3.83 (s, 3H) 3.94-4.07 (m, 4H)4.58-4.66 (m, 1H) 7.04 (s, 1H) 7.50 (s, 1H) 8.49 (s, 1H).

Intermediate 75.4: (4-Chloro-phenyl)-trimethyl-stannane

To a 1M solution of trimethyltin chloride in THF (92 ml, 92 mmol) wasslowly added a 1M solution of 4-chlorophenylmagnesium bromide in Et₂O(92 ml, 92 mmol) over a 40 min period at −10° C. so that the temperaturenever exceed 0° C. After the addition, the cooling bath was removed andthe resulting suspension was stirred at RT for 1 h. A saturated aqueoussolution of NH₄Cl (14 ml) was added followed by water until completedissolution of the precipitate. The mixture was transferred into aseparating funnel and extracted with Et₂O (3×). The combined organicfractions were dried over Na₂SO₄, filtered and evaporated to dryness.The resulting crude material was purified by Combi-Flash Companion™(Isco Inc.) column chromatography (SiO₂; isocratic elution withcyclohexane) to yield the title compound (24.47 g, 89 mmol, 97%) as acolorless oil. TLC: R_(F)=0.76 (cyclohexane/AcOEt 95:5); HPLC:^(A)t_(Ret)=3.25 min; ¹H NMR (400 MHz, CDCl₃): 0.31 (s, 9H) 7.32-7.36(m, 2H) 7.41-7.45 (m, 2H).

Intermediate 75.5:{2-[(S)-(4-Chloro-phenyl)-((S)-2-methyl-propane-2-sulfinylamino)-methyl]-4-isopropoxy-5-methoxy-phenyl}-aceticacid ethyl ester

A 250-mL flask was charged with Intermediate 75.3 (10.97 g, 28.6 mmol)and anhydrous THF (50 ml) then evacuated under vacuum and back-filledwith argon (3×). Intermediate 75.4 (15.75 g, 57.2 mmol) andbis(acetonitrile)(1,5-cyclooctadiene)rhodium(I)tetrafluoro-borate (1.09g, 2.86 mmol) were successively added at RT and the resulting orangesuspension was heated at 60° C. and stirred for 2 h. Additionalbis(acetonitrile)(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate (1.09g, 2.86 mmol) was added at 60° C. and the mixture was further stirredfor 4 h. The reaction mixture was cooled to RT, diluted with AcOEt andwashed with water. The organic phase was dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, heptane/AcOEt 95:5→3:7) to yield the title compound (3.96 g,7.98 mmol, 28%) as a brownish resin. TLC: R_(F)=0.29 (heptane/AcOEt1:1); HPLC: ^(A)t_(Ret)=2.70 min; LC-MS: m/z 496.3 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆): 1.10-1.19 (m, 15H), 1.23 (d, J=5.9, 3H), 3.57 (d, J=16.4,1H), 3.68 (d, J=16.1, 1H), 3.73 (s, 3H), 3.93-4.05 (m, 2H), 4.37-4.45(m, 1H), 5.62 (d, J=6.1, 1H), 5.82 (d, J=6.1, 1H), 6.82 (s, 1H), 6.94(s, 1H), 7.25-7.30 (m, 2H), 7.36-7.41 (m, 2H).

Intermediate 75.6:(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

A solution of Intermediate 75.5 (3.96 g, 7.98 mmol) in 1.25M HCl in MeOH(128 ml) was stirred at RT for 30 min. The reaction mixture wasevaporated to dryness and the resulting residue was dissolved in MeOH(40 ml). Et₃N (5.56 ml, 39.9 mmol) was added at RT then the mixture wasstirred for 15 min and evaporated to dryness. The resulting crudematerial was purified by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, [heptane/DCM 1:1]/TBME 9:1→100%TBME) to yield the title compound (2.51 g, 7.24 mmol, 91%, ee 92%) as anoff-white solid. TLC: R_(F)=0.13 (heptane/DCM/TBME 1:1:2); HPLC:^(A)t_(Ret)=2.03 min; LC-MS: m/z 346.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 1.16 (d, J=6.1, 3H), 1.21 (d, J=6.1, 3H), 3.36 (d, J=19.8,1H), 3.51 (d, J=19.8, 1H), 3.72 (s, 3H), 4.40 (spt, J=6.1, 1H), 5.55 (d,J=3.4, 1H), 6.79 (s, 1H), 6.84 (s, 1H), 7.26-7.33 (m, 2H), 7.35-7.42 (m,2H), 8.49 (d, J=3.9, 1H).

Intermediate 75.7:{4-[(4-Iodo-phenylamino)-methyl]-trans-cyclohexyl}-carbamic acidtert-butyl ester

To a solution of 4-iodo-phenylamine (1 g, 4.57 mmol) in DCM (25 ml) weresuccessively added AcOH (0.523 ml, 9.13 mmol),(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.14 g, 5.02 mmol)and NaBH(OAc)₃ (1.94 g, 9.13 mmol) at RT. The reaction mixture wasstirred at RT for 1 h then diluted with Et₂O and washed successivelywith a 2M aqueous HCl solution and a 2M aqueous Na₂CO₃ solution. Theorganic phase was dried over Na₂SO₄, filtered and evaporated to dryness.The resulting crude material was purified by Combi-Flash Companion™(Isco Inc.) column chromatography (SiO₂; gradient elution, heptane/AcOEt95:5→1:1) to yield the title compound (1.56 g, 3.62 mmol, 79%) as acolorless solid. TLC: R_(F)=0.72 (heptane/AcOEt 1:1); HPLC:^(A)t_(Ret)=2.64 min; LC-MS: m/z 431.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.87-1.03 (m, 2H), 1.03-1.17 (m, 2H), 1.32-1.48 (m, 1H), 1.37(s, 9H), 1.70-1.86 (m, 4H), 2.76-2.86 (m, 2H), 3.08-3.25 (m, 1H),5.77-5.89 (m, 1H), 6.34-6.46 (m, 2H), 6.59-6.71 (m, 1H), 7.24-7.35 (m,2H).

Intermediate 75.8:(Trans-4-dimethylamino-cyclohexylmethyl)-(4-iodo-phenyl)-methyl-amine

To a solution of Intermediate 75.7 (200 mg, 0.47 mmol) in DCM (2 ml) wasadded TFA (1.07 ml, 13.94 mmol) at RT. The reaction mixture was stirredat RT for 45 min then evaporated to dryness. The resulting residue wasdissolved in DCM (5 ml) and AcOH (0.221 ml, 3.86 mmol), formaldehyde(37% in water, 0.289 ml, 3.86 mmol) and NaBH(OAc)₃ (818 mg, 3.86 mmol)were successively added at RT. The reaction mixture was stirred at RTfor 1 h then diluted with DCM and washed with a 2M aqueous Na₂CO₃solution (2×). The organic phase was dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, [heptane/DCM 1:1]/TBME containing 5% of 7M NH₃ in MeOH95:5→100% TBME containing 5% of 7M NH₃ in MeOH) to yield the titlecompound (141 mg, 0.38 mmol, 83%) as a light yellow oil. TLC: R_(F)=0.32(heptane/DCM/TBME containing 5% of 7M NH₃ in MeOH 1:1:2); HPLC:^(A)t_(Ret)=1.42 min; LC-MS: m/z 373.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.89-1.01 (m, 2H), 1.02-1.14 (m, 2H), 1.51-1.63 (m, 1H),1.63-1.72 (m, 2H), 1.73-1.82 (m, 2H), 2.02-2.11 (m, 1H), 2.13 (s, 6H),2.87 (s, 3H), 3.12 (d, J=7.1, 2H), 6.46-6.53 (m, 2H), 7.35-7.43 (m, 2H).

Example 76(S)-1-(4-Chloro-phenyl)-2-{4-[(trans-4-dimethylamino-cyclohexylmethyl)-ethyl-amino]-phenyl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (TFA salt, 18.8 mg, 0.026 mmol, 36%) was obtained asa yellow solid from Intermediate 75.6 (25 mg, 0.072 mmol) andIntermediate 76.3 (41.9 mg, 0.108 mmol) analogously to Example 75.Purification of the crude material was performed by reverse phaseprep-HPLC (Waters system). HPLC: ^(B)t_(Ret)=1.75 min; LC-MS: m/z 604.5[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.96-1.11 (m, 5H), 1.20 (d, J=5.9,3H), 1.24 (d, J=6.1, 3H), 1.30-1.45 (m, 2H), 1.54-1.70 (m, 1H),1.78-1.89 (m, 2H), 1.92-2.03 (m, 2H), 2.67-2.74 (2s, 6H), 3.02-3.16 (m,3H), 3.33 (q, J=6.8, 2H), 3.53-3.60 (m, 1H), 3.73 (s, 3H), 3.88 (d,J=19.8, 1H), 4.40-4.50 (m, 1H), 5.94 (s, 1H), 6.54-6.62 (m, 2H), 6.84(s, 1H), 6.86-6.93 (m, 2H), 7.06 (s, 1H), 7.33-7.41 (m, 4H).

Intermediate 76.1:(4-{[Ethyl-(4-iodo-phenyl)-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

To a suspension of Intermediate 75.7 (100 mg, 0.232 mmol) and K₂CO₃(64.2 mg, 0.465 mmol) in DMF (1 ml) was added iodoethane (0.192 ml, 2.33mmol) at RT. The reaction mixture was heated at 60° C., vigorouslystirred for 14 h then cooled to RT and poured into water. The mixturewas extracted with Et₂O (2×) and the combined organic fractions weredried over Na₂SO₄, filtered and evaporated to dryness to yield the crudetitle compound (104 mg, 0.23 mmol, quant.) as a brownish solid which wasused in the next step without further purification. HPLC:^(B)t_(Ret)=2.76 min; API-MS: m/z 459.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.92-1.14 (m, 7H), 1.37 (s, 9H), 1.45-1.59 (m, 1H), 1.61-1.82(m, 4H), 3.05 (d, J=7.1, 2H), 3.10-3.24 (m, 1H), 3.31 (q, J=6.8, 2H),6.44-6.55 (m, 2H), 6.60-6.69 (m, 1H), 7.33-7.42 (m, 2H).

Intermediate 76.2:(Trans-4-dimethylamino-cyclohexylmethyl)-ethyl-(4-iodo-phenyl)-amine.

The title compound (45 mg, 0.116 mmol, 54%) was obtained as a colorlessoil from Intermediate 76.1 (101 mg, 0.22 mmol) analogously toIntermediate 75.8. Purification of the crude material was performed byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, [heptane/DCM 1:1]/TBME containing 5% of 7M NH₃ in MeOH 9:1→100%TBME containing 5% of 7M NH₃ in MeOH). HPLC: ^(B)t_(Ret)=1.30 min;API-MS: m/z 387.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.89-1.17 (m, 7H),1.47-1.65 (m, 1H), 1.67-1.85 (m, 4H), 2.14 (s, 6H), 3.04 (d, J=7.1, 2H),3.26-3.39 (m, 3H), 6.44-6.52 (m, 2H), 7.32-7.41 (m, 2H).

Example 77N-{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl-trans-cyclohexyl}-methanesulfonamide

To a solution of Intermediate 77.3 (20 mg, 0.036 mmol) in MeCN (0.5 ml)were successively added Et₃N (0.015 ml, 0.107 mmol) and methanesulfonylchloride (8.2 mg, 0.071 mmol) at RT. The reaction mixture was stirred atRT for 1 h then directly subjected to purification by reverse phaseprep-HPLC (Waters system) to yield the title compound (TFA salt, 5 mg,0.007 mmol, 19%) as a reddish solid. HPLC: ^(A)t_(Ret)=2.15 min; LC-MS:m/z 640.7 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.94-1.21 (m, 4H), 1.19 (d,J=5.9, 3H), 1.24 (d, J=6.1, 3H), 1.49-1.61 (m, 1H), 1.61-1.71 (m, 2H),1.84-1.93 (m, 2H), 2.85-2.90 (m, 6H), 2.96-3.20 (m, 3H), 3.57 (d,J=19.8, 1H), 3.73 (s, 3H), 3.89 (d, J=19.8, 1H), 4.40-4.50 (m, 1H), 5.95(s, 1H), 6.54-6.62 (m, 2H), 6.84 (s, 1H), 6.87-6.93 (m, 2H), 6.96 (d,J=7.3, 1H), 7.04 (s, 1H), 7.35 (s, 4H).

Intermediate 77.1:(4-{[(4-Iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

To a solution of Intermediate 75.7 (748 mg, 1.74 mmol) in DCM (15 ml)were successively added AcOH (0.199 ml, 3.48 mmol), formaldehyde (37% inwater, 0.259 ml, 3.48 mmol) and NaBH(OAc)₃ (737 mg, 3.48 mmol) at RT.The reaction mixture was stirred at RT for 2 h then diluted with DCM andwashed with a 2M aqueous Na₂CO₃ solution (2×). The organic phase wasdried over Na₂SO₄, filtered and evaporated to dryness. The resultingcrude material was purified by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, heptane/AcOEt 98:2→7:3) to yieldthe title compound (584 mg, 1.31 mmol, 76%) as a colorless solid. TLC:R_(F)=0.36 (heptane/AcOEt 3:1); HPLC: ^(A)t_(Ret)=2.76 min; LC-MS: m/z445.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.90-1.13 (m, 4H), 1.36 (s,9H), 1.48-1.66 (m, 3H), 1.69-1.81 (m, 2H), 2.87 (s, 3H), 3.08-3.21 (m,1H), 3.12 (d, J=7.1, 2H), 6.45-6.54 (m, 2H), 6.68 (d, J=8.1, 1H),7.34-7.43 (m, 2H).

Intermediate 77.2:{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-carbamicacid tert-butyl ester

The title compound (1.03 g, 1.56 mmol, 69%) was obtained as a brownishsolid from Intermediate 75.6 (780 mg, 2.26 mmol) and Intermediate 77.1(1.2 g, 2.71 mmol) analogously to Example 75. Purification of the crudematerial was performed by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, [heptane/DCM 1:1]/TBME95:5→4:6). HPLC: ^(A)t_(Ret)=2.63 min; LC-MS: m/z 662.7 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆): 0.91-1.12 (m, 4H), 1.19 (d, J=6.1, 3H), 1.24 (d,J=6.1, 3H), 1.36 (s, 9H), 1.48-1.60 (m, 1H), 1.59-1.68 (m, 2H),1.70-1.80 (m, 2H), 2.87 (s, 3H), 3.05-3.21 (m, 3H), 3.57 (d, J=20.1,1H), 3.73 (s, 3H), 3.89 (d, J=20.1, 1H), 4.40-4.50 (m, 1H), 5.94 (s,1H), 6.52-6.60 (m, 2H), 6.66 (d, J=7.8, 1H), 6.83 (s, 1H), 6.86-6.93 (m,2H), 7.04 (s, 1H), 7.35 (s, 4H).

Intermediate 77.3:(S)-2-{4-[(Trans-4-amino-cyclohexylmethyl)-methyl-amino]-phenyl}-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 77.2 (270 mg, 0.41 mmol) in DCM (2 ml) wasadded TFA (0.942 ml, 12.23 mmol) at RT. The reaction mixture was stirredat RT for 30 min then diluted with DCM and washed with a 2M aqueousNa₂CO₃ solution (2×). The organic phase was dried over Na₂SO₄, filteredand evaporated to dryness to yield the crude title compound (251 mg,0.41 mmol, quant.) as a brownish solid which was used in the next stepwithout further purification. HPLC: ^(A)t_(Ret)=1.77 min; LC-MS: m/z562.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.89-1.00 (m, 2H), 1.19 (d,J=5.9, 3H), 1.21-1.33 (m, 5H), 1.51-1.68 (m, 3H), 1.68-1.78 (m, 2H),2.39-2.47 (m, 1H), 2.87 (s, 3H), 3.06-3.14 (m, 2H), 3.57 (d, J=19.8,1H), 3.73 (s, 3H), 3.89 (d, J=19.6, 1H), 4.40-4.50 (m, 1H), 5.94 (s,1H), 6.52-6.60 (m, 2H), 6.84 (s, 1H), 6.86-6.93 (m, 2H), 7.04 (s, 1H),7.36 (s, 4H).

Example 78 Oxazole-4-carboxylic acid{4-[({4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-amide

To a solution of Intermediate 77.3 (20 mg, 0.036 mmol) in DMF (0.5 ml)were successively added 4-oxazolecarboxylic acid (4.8 mg, 0.043 mmol),Et₃N (0.010 ml, 0.071 mmol) and HATU (17.6 mg, 0.046 mmol) at RT. Thereaction mixture was heated at 50° C. and stirred for 14 h, then cooledto RT and directly subjected to purification by reverse phase prep-HPLC(Waters system) to yield the title compound (TFA salt, 11 mg, 0.014mmol, 40%) as a reddish solid. HPLC: ^(A)t_(Ret)=2.14 min; LC-MS: m/z657.7 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.99-1.14 (m, 2H), 1.19 (d,J=5.9, 3H), 1.24 (d, J=6.1, 3H), 1.27-1.42 (m, 2H), 1.54-1.66 (m, 1H),1.65-1.82 (m, 4H), 2.90 (s, 3H), 3.14 (d, J=6.6, 2H), 3.57 (d, J=19.8,1H), 3.73 (s, 3H), 3.89 (d, J=19.8, 1H), 4.40-4.50 (m, 1H), 5.96 (s,1H), 6.56-6.64 (m, 2H), 6.84 (s, 1H), 6.88-6.95 (m, 2H), 7.04 (s, 1H),7.36 (s, 4H), 7.96 (d, J=8.3, 1H), 8.49 (s, 1H), 8.58 (s, 1H).

Example 79(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 79.2 (49 mg, 0.063 mmol) in DCM (0.5 ml)was added TFA (0.097 ml, 1.261 mmol) at RT. The reaction mixture wasstirred at RT for 5 h and evaporated to dryness. The resulting residuewas dissolved in MeOH (0.5 ml) then Et₃N (0.088 ml, 0.63 mmol) was addedand the mixture was stirred at RT for 1 h. The reaction mixture wasdirectly subjected to purification by reverse phase prep-HPLC (Waterssystem) to yield the title compound (TFA salt, 19.4 mg, 0.026 mmol, 41%)as an off-white solid. HPLC: ^(A)t_(Ret)=1.76 min; LC-MS: m/z 645.7[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.90-1.04 (m, 2H), 1.08-1.20 (m, 2H),1.19 (d, J=6.1, 3H), 1.24 (d, J=6.1, 3H), 1.52-1.66 (m, 1H), 1.66-1.83(m, 4H), 2.20-2.31 (m, 1H), 2.55-2.63 (m, 2H), 2.88 (s, 3H), 3.00 (s,2H), 3.04-3.15 (m, 4H), 3.57 (d, J=20.1, 1H), 3.73 (s, 3H), 3.89 (d,J=19.8, 1H), 4.41-4.50 (m, 1H), 5.94 (s, 1H), 6.52-6.60 (m, 2H), 6.83(s, 1H), 6.86-6.94 (m, 2H), 7.04 (s, 1H), 7.36 (s, 4H), 7.66 (br. s.,1H).

Intermediate 79.1:{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexylamino}-aceticacid methyl ester

To a solution of Intermediate 77.3 (100 mg, 0.178 mmol) in DCM (1.5 ml)were successively added Et₃N (0.050 ml, 0.356 mmol) and methyl2-bromoacetate (0.018 ml, 0.196 mmol) at RT. The reaction mixture wasstirred at RT for 6 h then additional Et₃N (0.050 ml, 0.356 mmol) andmethyl 2-bromoacetate (0.018 ml, 0.196 mmol) were added. The mixture wasfurther stirred at RT for 24 h then diluted with DCM and washed withwater. The organic phase was dried over Na₂SO₄, filtered and evaporated.The resulting crude material was purified by Combi-Flash Companion™(Isco Inc.) column chromatography (SiO₂; gradient elution, DCM/[DCM/7MNH₃ in MeOH 9:1] 95:5→100% DCM/7M NH₃ in MeOH 9:1) to yield the titlecompound (75 mg, 0.118 mmol, 67%) as a yellow resin. TLC: R_(F)=0.68(DCM/7M NH₃ in MeOH 9:1); HPLC: ^(A)t_(Ret)=1.85 min; LC-MS: m/z 634.7[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.83-1.01 (m, 4H), 1.19 (d, J=6.1,3H), 1.24 (d, J=6.1, 3H), 1.51-1.69 (m, 3H), 1.74-1.86 (m, 2H),2.24-2.36 (m, 1H), 2.87 (s, 3H), 3.06-3.13 (m, 2H), 3.29-3.35 (m, 2H),3.57 (d, J=19.8, 1H), 3.61 (s, 3H), 3.73 (s, 3H), 3.89 (d, J=19.8, 1H),4.41-4.49 (m, 1H), 5.92-5.96 (m, 1H), 6.51-6.59 (m, 2H), 6.83 (s, 1H),6.86-6.92 (m, 2H), 7.04 (s, 1H), 7.35 (s, 4H).

Intermediate 79.2:((2-tert-Butoxycarbonylamino-ethyl)-{-[({4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

To a solution of Intermediate 79.1 (144 mg, 0.227 mmol) in DCM (2 ml)were successively added N-Boc-2-aminoacetaldehyde (72.3 mg, 0.454 mmol),AcOH (0.039 ml, 0.681 mmol) and NaBH(OAc)₃ (144 mg, 0.681 mmol) at RT.The suspension was stirred at RT for 1 h then diluted with DCM andwashed with a 2M aqueous Na₂CO₃ solution. The organic phase was driedover Na₂SO₄, filtered and evaporated. The resulting crude material waspurified by reverse phase prep-HPLC (Waters system). Fractionscontaining pure material were combined and concentrated under vacuum.The resulting aqueous mixture was basified by the addition of Na₂CO₃ 2Mand extracted with AcOEt. The organic layer was washed with brine, driedover Na₂SO₄, filtered and evaporated to dryness to yield the titlecompound (142.6 mg, 0.183 mmol, 81%) as a yellow solid. HPLC:^(A)t_(Ret)=2.20 min; LC-MS: m/z 777.9 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆): 0.89-0.99 (m, 2H), 1.02-1.12 (m, 2H), 1.17 (d, J=6.0, 3H),1.22 (d, J=6.0, 3H), 1.35 (s, 9H), 1.49-1.74 (m, 6H), 2.52-2.58 (m, 2H),2.85 (s, 3H), 2.86-2.93 (m, 2H), 3.05-3.10 (m, 2H), 3.28 (s, H),3.52-3.59 (m, 1H), 3.57 (s, 3H), 3.71 (s, 3H), 3.87 (d, J=19.8, 1H),4.39-4.48 (m, 1H), 5.93 (s, 1H), 6.44-6.50 (m, 1H), 6.51-6.58 (m, 2H),6.82 (s, 1H), 6.85-6.91 (m, 2H), 7.03 (s, 1H), 7.34 (s, 4H).

Example 80({4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-methyl-amino)-aceticacid methyl ester

To a solution of Intermediate 79.1 (22 mg, 0.035 mmol) in DCM (0.5 ml)were successively added AcOH (0.006 ml, 0.10 mmol), formaldehyde (37% inwater, 0.008 ml, 0.10 mmol) and NaBH(OAc)₃ (22.1 mg, 0.10 mmol) at RT.The reaction mixture was stirred at RT for 3 h then diluted with DCM andwashed with a 2M aqueous Na₂CO₃ solution (2×). The organic phase wasdried over Na₂SO₄, filtered and evaporated to dryness. The resultingcrude material was purified by reverse phase prep-HPLC (Waters system)to yield the title compound (TFA salt, 4.6 mg, 0.006 mmol, 17%) as acolorless solid. HPLC: ^(A)t_(Ret)=1.87 min; LC-MS: m/z 648.7 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆): 0.96-1.11 (m, 2H), 1.19 (d, J=5.9, 3H), 1.24 (d,J=5.9, 3H), 1.36-1.54 (m, 2H), 1.60-1.72 (m, 1H), 1.74-1.84 (m, 2H),1.92-2.06 (m, 2H), 2.76 (br. s., 3H), 2.89 (s, 3H), 3.10-3.16 (m, 2H),3.16-3.27 (m, 1H), 3.57 (d, J=20.1, 1H), 3.73 (s, 3H), 3.78 (s, 3H),3.90 (d, J=20.1, 1H), 4.04-4.15 (m, 1H), 4.25-4.35 (m, 1H), 4.41-4.50(m, 1H), 5.94 (s, 1H), 6.54-6.62 (m, 2H), 6.84 (s, 1H), 6.87-6.94 (m,2H), 7.03 (s, 1H), 7.36 (s, 4H).

Example 81(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[methyl-(trans-4-morpholin-4-yl-cyclohexylmethyl)-amino]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 77.3 (20 mg, 0.036 mmol) in DMF (0.5 ml)were successively added K₂CO₃ (24.59 mg, 0.178 mmol) andbis(2-bromoethyl)ether (0.022 ml, 0.178 mmol) at RT. The reactionmixture was stirred at RT for 14 h then diluted with AcOEt and washedwith water. The organic phase was dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byreverse phase prep-HPLC (Waters system) to yield the title compound (TFAsalt, 14.3 mg, 0.019 mmol, 54%) as a reddish solid. HPLC:^(A)t_(Ret)=1.86 min; LC-MS: m/z 632.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.96-1.12 (m, 2H), 1.19 (d, J=6.1, 3H), 1.24 (d, J=6.1, 3H),1.30-1.44 (m, 2H), 1.57-1.72 (m, 1H), 1.75-1.86 (m, 2H), 2.01-2.11 (m,2H), 2.89 (s, 3H), 3.02-3.19 (m, 5H), 3.32-3.41 (m, 2H), 3.57 (d,J=20.1, 1H), 3.61-3.70 (m, 2H), 3.73 (s, 3H), 3.90 (d, J=20.1, 1H),3.95-4.03 (m, 2H), 4.40-4.51 (m, 1H), 5.94 (s, 1H), 6.54-6.62 (m, 2H),6.84 (s, 1H), 6.87-6.94 (m, 2H), 7.03 (s, 1H), 7.36 (s, 4H).

Example 821-{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-piperazine-2,5-dione

To a solution of the crude Intermediate 82.1 (45.1 mg) in DCM (0.5 ml)was added TFA (0.182 ml, 2.36 mmol) at RT. The reaction mixture wasstirred at RT for 45 min and evaporated to dryness. The resultingresidue was dissolved in MeOH (0.5 ml) then Et₃N (0.066 ml, 0.47 mmol)was added and the mixture was stirred at RT for 1 h. The reactionmixture was directly subjected to purification by reverse phaseprep-HPLC (Waters system) to yield the title compound (TFA salt, 18 mg,0.023 mmol, 49% over 2 steps) as a colorless solid. HPLC:^(A)t_(Ret)=1.99 min; LC-MS: m/z 659.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 1.01-1.15 (m, 2H), 1.19 (d, J=5.9, 3H), 1.24 (d, J=6.1, 3H),1.39-1.56 (m, 4H), 1.57-1.68 (m, 1H), 1.68-1.78 (m, 2H), 2.89 (s, 3H),3.13 (d, J=6.6, 2H), 3.57 (d, J=20.1, 1H), 3.69-3.78 (m, 7H), 3.90 (d,J=19.8, 2H), 4.09-4.19 (m, 1H), 4.41-4.51 (m, 1H), 5.95 (s, 1H),6.54-6.64 (m, 2H), 6.84 (s, 1H), 6.87-6.95 (m, 2H), 7.04 (s, 1H), 7.36(s, 4H), 8.09 (br. s., 1H).

Intermediate 82.1:((2-tert-Butoxycarbonylamino-acetyl)-{4-[({4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

To a solution of Intermediate 79.1 (30 mg, 0.047 mmol) in DMF (0.5 ml)were successively added tert-butoxycarbonylamino-acetic acid (9.12 mg,0.052 mmol), Et₃N (0.013 ml, 0.095 mmol) and HATU (23.38 mg, 0.061 mmol)at RT. The reaction mixture was heated at 50° C. and stirred for 2 h30,then cooled to RT, diluted with Et₂O and washed with water (2×). Theorganic phase was dried over Na₂SO₄, filtered and evaporated to drynessto yield the crude title compound (45.1 mg) as a yellow resin, which wasused in the next step without further purification. HPLC:^(A)t_(Ret)=2.67 min; LC-MS: m/z 791.3 [M+H]⁺.

Example 832-(Carbamoylmethyl-{4-[({4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-acetamide

A suspension of Intermediate 77.3 (20 mg, 0.036 mmol), 2-bromoacetamide(15.7 mg, 0.114 mmol) and K₂CO₃ (14.8 mg, 0.107 mmol) in DMF (0.5 ml)was stirred at RT for 14 h, then diluted with DCM and washed with water.The organic phase was dried over Na₂SO₄, filtered and evaporated todryness. The resulting crude material was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,DCM/[DCM/7M NH₃ in MeOH 9:1] 95:5→100% DCM/7M NH₃ in MeOH 9:1) to yieldthe title compound (17 mg, 0.025 mmol, 71%) as a colorless solid. TLC:R_(F)=0.16 (DCM/7M NH₃ in MeOH 9:1); HPLC: ^(A)t_(Ret)=1.81 min; LC-MS:m/z 676.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.87-1.01 (m, 2H),1.05-1.16 (m, 2H), 1.19 (d, J=6.1, 3H), 1.24 (d, J=6.1, 3H), 1.50-1.64(m, 1H), 1.64-1.81 (m, 4H), 2.27-2.38 (m, 1H), 2.86 (s, 3H), 2.97 (s,4H), 3.05-3.12 (m, 2H), 3.57 (d, J=19.8, 1H), 3.73 (s, 3H), 3.89 (d,J=19.8, 1H), 4.40-4.50 (m, 1H), 5.94 (s, 1H), 6.52-6.59 (m, 2H), 6.83(s, 1H), 6.85-6.92 (m, 2H), 7.04 (s, 1H), 7.06-7.13 (m, 2H), 7.35 (s,4H), 7.66-7.73 (m, 2H).

Example 84(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(3-oxo-[1,4]diazepan-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

To a solution of the crude Intermediate 84.1 (41.9 mg) in MeOH (0.5 ml)were successively added NH₄Cl (22.97 mg, 0.429 mmol) and ammoniumformate (6.02 mg, 0.095 mmol). The reaction flask was evacuated undervacuum and flushed with argon (3×) then Pd/C (1.016 mg, 0.01 mmol) wasadded, the flask was sealed and the reaction mixture was stirred at RTfor 2 h. Additional ammonium formate (18.05 mg, 0.286 mmol) was addedand the reaction mixture was further stirred at RT for 1 h. Thesuspension was filtered and the filtrate evaporated to dryness. Theresulting residue was dissolved in AcOEt and washed with water. Theorganic phase was dried over Na₂SO₄, filtered and evaporated to dryness.The resulting residue was dissolved in MeOH (0.5 ml) then Et₃N (0.062ml, 0.44 mmol) was added and the mixture was stirred at RT for 14 h. Thereaction mixture was directly subjected to purification by reverse phaseprep-HPLC (Waters system) to yield the title compound (TFA salt, 12.8mg, 0.017 mmol, 35% from Intermediate 79.1) as a colorless solid. HPLC:^(A)t_(Ret)=1.81 min; LC-MS: m/z 659.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.97-1.13 (m, 2H), 1.19 (d, J=6.1, 3H), 1.24 (d, J=6.1, 3H),1.37-1.54 (m, 2H), 1.61-1.74 (m, 1H), 1.74-1.90 (m, 3H), 1.90-2.10 (m,3H), 2.89 (s, 3H), 3.08-3.15 (m, 2H), 3.16-3.51 (m, 5H), 3.57 (d,J=20.1, 1H), 3.73 (s, 3H), 3.75-3.83 (m, 1H), 3.91 (d, J=19.6, 1H),4.09-4.21 (m, 1H), 4.40-4.52 (m, 1H), 5.94 (s, 1H), 6.53-6.62 (m, 2H),6.84 (s, 1H), 6.87-6.95 (m, 2H), 7.03 (s, 1H), 7.36 (s, 4H), 8.30-8.40(m, 1H).

Intermediate 84.1:((3-Benzyloxycarbonylamino-propyl)-{-[({4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino]-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

To a solution of Intermediate 79.1 (30 mg, 0.047 mmol) in DCM (0.5 ml)were successively added 3-[(benzyloxycarbonyl)-amino]propionalehyde(11.76 mg, 0.057 mmol), AcOH (0.005 ml, 0.095 mmol) and NaBH(OAc)₃(20.05 mg, 0.095 mmol) at RT. The suspension was stirred at RT for 1 hthen diluted with DCM and washed with a 2M aqueous Na₂CO₃ solution. Theorganic phase was dried over Na₂SO₄, filtered and evaporated to drynessto give the crude title compound (41.9 mg) as a yellow resin, which wasused in the next step without further purification. HPLC:^(A)t_(Ret)=2.25 min; LC-MS: m/z 825.4 [M+H]⁺.

Example 85(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

A solution of the crude Intermediate 85.1 (135 mg) and formaldehyde (37%in water, 0.156 ml, 2.1 mmol) in EtOH (3 ml) was heated at 80° C. andstirred for 4 h. The reaction mixture was cooled to RT and evaporated todryness. The resulting residue was heated at 150° C. for 14 h undervacuum then cooled to RT and purified by reverse phase prep-HPLC (Waterssystem) to yield the title compound (TFA salt, 22.5 mg, 0.030 mmol, 14%from Intermediate 79.1) as a yellow solid. HPLC: ^(A)t_(Ret)=1.89 min;LC-MS: m/z 631.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 1.07-1.18 (m, 2H),1.20 (d, J=6.1, 3H), 1.26 (d, J=6.1, 3H), 1.33-1.47 (m, 2H), 1.71-1.85(m, 1H), 1.87-1.96 (m, 2H), 2.10-2.21 (m, 2H), 2.96 (s, 3H), 3.21 (d,J=6.6, 2H), 3.26-3.29 (m, 1H), 3.72 (d, J=20.3, 1H), 3.84 (s, 3H), 3.95(s, 2H), 4.03 (d, J=20.3, 1H), 4.39-4.49 (m, 1H), 4.80 (s, 2H), 5.87 (s,1H), 6.64-6.71 (m, 2H), 6.78 (s, 1H), 6.85-6.93 (m, 3H), 7.13-7.20 (m,2H), 7.25-7.31 (m, 2H).

Intermediate 85.1:2-{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexylamino}-acetamide

In a sealed reaction flask, a solution of Intermediate 79.1 (134 mg,0.21 mmol) in a 7M NH₃ solution in MeOH (3.35 ml) was heated at 70° C.and stirred for 14 h. The reaction mixture was cooled to RT andevaporated to dryness to yield the crude title compound (135 mg) as anorange resin, which was used in the next step without furtherpurification. HPLC: ^(A)t_(Ret)=1.85 min; LC-MS: m/z 619.3 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD): 0.95-1.14 (m, 4H), 1.21 (d, J=5.9, 3H), 1.26 (d,J=6.1, 3H), 1.64-1.80 (m, 3H), 1.90-1.98 (m, 2H), 2.33-2.44 (m, 1H),2.93 (s, 3H), 3.12-3.19 (m, 2H), 3.26 (s, 2H), 3.35 (s, 2H), 3.71 (d,J=20.1, 1H), 3.84 (s, 3H), 4.02 (d, J=20.5, 1H), 4.40-4.49 (m, 1H), 5.86(s, 1H), 6.59-6.65 (m, 2H), 6.79 (s, 1H), 6.82-6.89 (m, 3H), 7.13-7.18(m, 2H), 7.25-7.31 (m, 2H).

Example 86

Compounds 86a to 86e were obtained analogously to Example 75 by reactionof Intermediate 75.6 (or analogues preparted similarly) with variousbromo- or iodo-aryl intermediates prepared analogously to Intermediate75.8. Compounds 86f and 86g were obtained analogously to Example 77 andExample 78 by reaction of Intermediate 77.3 (or analogues preparedsimilarly) with various sulfonyl chlorides, acyl chlorides or carboxylicacids. Compounds 86h and 86i were obtained analogously to Example 81 byreaction of Intermediate 77.3 (or analogues prepared similarly) withvarious bis-halogenated alkyl analogues.

# Structure Name/HPLC/MS/NMR 86a

(S)-1-(4-Chloro-phenyl)-2-{5-[(trans-4-dimethylamino-cyclohexylmethyl)-methyl-amino]-pyridin-2-yl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1 83;LC-MS: m/z 591.6 [M + H]⁺. 86b

(S)-1-(4-Chloro-phenyl)-2-{4-[(trans-4-dimethylamino-cyclohexylmethyl)-methyl-amino]-3-methyl-phenyl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one NVP-CEX461-Al-1 HPLC:^(A)t_(Ret) = 1.61; LC-MS: m/z 604.7 [M + H]⁺. 86c

(S)-1-(4-Chloro-phenyl)-2-{6-[(trans-4-dimethylamino-cyclohexylmethyl)-methyl-amino]-pyridin-3-yl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.56; LC-MS: m/z591.7 [M + H]⁺. 86d

(S)-1-(4-Chloro-phenyl)-2-{4-[(trans-4-dimethylamino-cyclohexylmethyl)-methyl-amino]-3-fluoro-phenyl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.98;LC-MS: m/z 608.7 [M + H]⁺. 86e

(S)-1-(4-Chloro-phenyl)-2-{4-[(trans-4-dimethylamino-cyclohexylmethyl)-methyl-amino]-2-methoxy-phenyl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.92;LC-MS: m/z 620.3 [M + H]⁺. 86f

Ethanesulfonic acid {4-[({4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4- dihydro-1H-isoquinolin-2-yl]-phenyl}- methyl-amino)-methyl]-trans-cyclohexyl}-amide. HPLC: ^(A)t_(Ret) = 2.25; LC-MS: m/z 654.7 [M + H]⁺. 86g

N-{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-propionamide. HPLC: ^(A)t_(Ret) = 2.13; LC-MS:m/z 618.3 [M + H]⁺. 86h

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[methyl-(trans-4-pyrrolidin-1-yl-cyclohexyl-methyl)-amino]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.89; LC-MS: m/z616.4 [M + H]⁺. 86i

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[methyl-(trans-4-piperidin-1-yl-cyclohexyl-methyl)-amino]-phenyl}-1,4- dihydro-2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.92; LC-MS: m/z 630.4 [M + H]⁺.

Example 87(S)-1-(4-Chloro-phenyl)-2-{4-[(S)-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-ethyl]-phenyl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (TFA salt, 11.9 mg, 0.017 mmol, 20%) was obtained asa light yellow solid from Intermediate 75.6 (30 mg, 0.087 mmol) andIntermediate 87.1 (41.4 mg, 0.13 mmol) analogously to Example 75.Purification of the crude material was performed by reverse phaseprep-HPLC (Waters system). HPLC: ^(A)t_(Ret)=1.90 min; LC-MS: m/z 583.5[M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 1.23 (d, J=5.9, 3H), 1.28 (d, J=6.1,1H), 1.53 (d, J=6.6, 1H), 3.21 (br. s., 8H), 3.77 (d, J=20.3, 1H), 3.87(s, 3H), 4.05 (d, J=20.3, 1H), 4.10-4.19 (m, 1H), 4.42-4.52 (spt, J=5.9,1H), 6.02 (s, 1H), 6.83 (s, 1H), 6.90 (s, 1H), 7.15-7.23 (m, 4H),7.28-7.34 (m, 2H), 7.41-7.47 (m, 2H).

Intermediate 87.1: 4-[(S)-1-(4-Bromo-phenyl)-ethyl]-thiomorpholine1,1-dioxide

A solution of (S)-1-(4-bromophenyl)ethanamine (0.144 ml, 1.0 mmol) andvinylsulfonylethene (0.100 ml, 1.0 mmol) in EtOH (4.0 ml) was heated at100° C. and stirred for 3 h. The reaction mixture was cooled to RT andevaporated to dryness. The resulting crude material was purified byCombi-Flash Companion™ (Isco Inc.) column chromatography (gradientelution, heptane AcOEt 95:5 to 4:6) to yield the title compound (256 mg,0.804 mmol, 80% yield) as a colorless oil which crystallized on standinginto a colorless solid. TLC: R_(F)=0.40 (heptane AcOEt 1:1); HPLC:^(B)t_(Ret)=1.29 min; LC-MS: m/z 320.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃):1.39 (d, J=6.8, 3H), 2.92-3.09 (m, 8H), 3.76 (q, J=6.8, 1H), 7.19-7.26(m, 2H), 7.45-7.53 (m, 2H).

Example 88(S)-2-{4-[(S)-1-(4-Acetyl-piperazin-1-yl)-ethyl]-phenyl}-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (TFA salt, 18.3 mg, 0.027 mmol, 26%) was obtainedfrom Intermediate 75.6 (36 mg, 0.104 mmol) and Intermediate 88.3 (48.6mg, 0.156 mmol) analogously to Example 75. Purification of the crudematerial was performed by reverse phase prep-HPLC (Waters system). HPLC:^(A)t_(Ret)=1.76 min; LC-MS: m/z 576.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 1.22 (d, J=6.1, 3H), 1.25 (d, J=5.9, 3H), 1.53-1.68 (m, 3H),2.01 (br. s., 3H), 2.69-3.20 (m, 4H), 3.56-3.69 (m, 2H), 3.73 (s, 3H),3.86 (d, J=19.8, 1H), 3.90-4.08 (m, 1H), 4.36-4.61 (m, 3H), 6.17 (s,1H), 6.87 (s, 1H), 7.13 (s, 1H), 7.30-7.42 (m, 6H), 7.44-7.54 (m, 2H).

Intermediate 88.1:1-[(S)-1-(4-Bromo-phenyl)-ethyl]-4-(toluene-4-sulfonyl)-piperazine

A mixture of (S)-1-(4-bromophenyl)ethanamine (0.36 ml, 2.50 mmol) andN,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (864 mg, 2.62 mmol) inDIPEA (0.873 ml, 5.0 mmol) was heated at 125° C. and stirred for 20 h.The reaction mixture was cooled to RT then diluted into DCM (30 ml) andwashed with Na₂CO₃ 2M in water (40 ml). The aqueous phase was furtherextracted with DCM (3×20 ml) and the combined organic fractions weredried over Na₂SO₄, filtered and evaporated to dryness. AcOEt was addedin small portions into a hot mixture of the crude in heptane untilcomplete dissolution. The mixture was allowed to cooled to RT duringwhich time precipitation occurred. The mixture was cooled to 0° C. (icebath) for 30 min then filtered. The solid was washed with heptane, driedunder air and finally under high vacuum to yield the title compound (810mg, 1.91 mmol, 77% yield) as a brownish solid. HPLC: ^(A)t_(Ret)=1.66min; LC-MS: m/z 425.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃): 1.29 (d, J=6.8,3H), 2.41-2.50 (m, 5H), 2.52-2.61 (m, 2H), 2.93-3.05 (m, 4H), 3.34 (q,J=6.7, 1H), 7.09-7.16 (m, 2H), 7.31-7.37 (m, 2H), 7.39-7.44 (m, 2H),7.61-7.66 (m, 2H).

Intermediate 88.2: 1-[(S)-1-(4-Bromo-phenyl)-ethyl]-piperazine

To a solution of Intermediate 88.1 (802 mg, 1.89 mmol) in TFA (1.46 ml,18.95 mmol) was added H₂SO₄ (0.707 ml, 13.26 mmol) at RT. The mixturewas heated at 75° C. and stirred for 6 h then cooled to RT, diluted withAcOEt and carefully washed with Na₂CO₃ 2M in water (2×) and brine. Theorganic layer was dried over Na₂SO₄, filtered and evaporated to drynessto yield the crude title compound (479.6 mg, 1.728 mmol, 91% yield) asan orange oil which was used in the next step without furtherpurification. HPLC: ^(A)t_(Ret)=0.86 min; LC-MS: m/z 269.5 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃): 1.33 (d, J=6.6, 3H), 2.29-2.39 (m, 2H), 2.40-2.53(m, 2H), 2.84-2.90 (m, 4H), 3.32 (q, J=6.8, 1H), 7.18-7.24 (m, 2H),7.41-7.48 (m, 2H).

Intermediate 88.3:1-{4-[(S)-1-(4-Bromo-phenyl)-ethyl]-piperazin-1-yl}-ethanone

To a solution of Intermediate 88.2 (103 mg, 0.371 mmol) in DCM (1.8 ml)were successively added Et₃N (0.155 ml, 1.113 mmol) and acetyl chloride(0.066 ml, 0.928 mmol) at RT. The mixture was stirred at RT for 1 h thendiluted into AcOEt (20 ml) and washed with Na₂CO₃ 2M in water (10 ml).The organic phase was dried over Na₂SO₄, filtered and evaporated todryness. The resulting crude material was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,[heptane/DCM 1:1]/TBME containing 5% of 7M NH₃ in MeOH 95:5 to 1:1) toyield the title compound (108 mg, 0.347 mmol, 93% yield) as a lightyellow oil. HPLC: ^(A)t_(Ret)=1.01 min; LC-MS: m/z 311.4 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃): 1.35 (d, J=6.6, 3H), 2.07 (s, 3H), 2.29-2.54 (m, 4H),3.37 (q, J=6.8, 1H), 3.43 (t, J=5.1, 2H), 3.52-3.68 (m, 2H), 7.17-7.24(m, 2H), 7.43-7.49 (m, 2H).

Example 89(R)-1-((S)-1-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-pyrrolidine-2-carboxylicacid methylamide

To a solution of Intermediate 89.4 (TFA salt, 8.7 mg, 0.013 mmol) in DMF(0.5 ml) were successively added methylamine (2M in THF, 0.077 ml, 0.155mmol), Et₃N (0.004 ml, 0.031 mmol) and HATU (11.8 mg, 0.031 mmol) at RT.The reaction mixture was heated at 50° C. and stirred for 14 h, thencooled to RT and directly subjected to purification by reverse phaseprep-HPLC (Waters system) to yield the title compound (TFA salt, 4.8 mg,0.007 mmol, 54%) as a colorless solid. HPLC: ^(A)t_(Ret)=1.76 min;LC-MS: m/z 576.5 [M+H]⁺.

Intermediate 89.1:(R)-1-[(S)-1-(4-Bromo-phenyl)-ethyl]-pyrrolidine-2-carboxylic acidmethyl ester

and

Intermediate 89.2:(S)-1-[(S)-1-(4-Bromo-phenyl)-ethyl]-pyrrolidine-2-carboxylic acidmethyl ester

The following procedure was adapted from W. A. J. Starmans, R. W. A.Walgers, L. Thijs, R. de Gelder, J. M. M. Smits, and B. Zwanenburg,Tetrahedron 54 (1998) 4991-5004. To a mixture of methyl2,5-dibromopentanoate (0.401 ml, 2.56 mmol) and K₂CO₃ (706 mg, 5.11mmol) in MeCN (7 ml) and water (0.7 ml) was added dropwise a solution of(S)-1-(4-bromophenyl)ethanamine (0.405 ml, 2.81 mmol) in MeCN (3.5 ml)at 80° C. After the addition, the reaction mixture was further stirredat 80° C. for 14 h then cooled to RT, diluted into AcOEt (50 ml) andwashed with water (40 ml). The aqueous phase was further extracted withAcOEt and the combined organic fractions were dried over Na₂SO₄,filtered and evaporated to dryness. The resulting crude material waspurified and both diastereoisomers separated by reversed phase prep-HPLC(gradient elution, MeCN/water containing 20 mM ammonium formate).Fractions containing pure material were combined and concentrated undervacuum. The resulting aqueous mixture was basified by the addition ofNa₂CO₃ 2M and extracted with AcOEt. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and evaporated to dryness to yieldthe title compounds as light yellow oils. Intermediate 89.1:240 mg, 0.77mmol, 30%; HPLC: ^(A)t_(Ret)=1.15 min, ^(C)t_(Ret)=4.07 min; LC-MS: m/z314.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃): 1.38 (d, J=6.6, 3H), 1.76-1.99(m, 3H), 2.04-2.16 (m, 1H), 2.52 (q, J=8.1, 1H), 3.05-3.13 (m, 1H), 3.47(dd, J=9.4, 3.5, 1H), 3.51 (s, 3H), 3.66 (q, J=6.6, 1H), 7.21-7.26 (m,2H), 7.39-7.45 (m, 2H). Intermediate 89.2: 222 mg, 0.71 mmol, 28%; HPLC:^(A)t_(Ret)=1.15 min, ^(C)t_(Ret)=5.18 min; LC-MS: m/z 314.4 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃): 1.36 (d, J=6.8, 3H), 1.73-1.84 (m, 1H), 1.84-1.96(m, 2H), 2.03-2.14 (m, 1H), 2.54-2.63 (m, 1H), 2.93-3.02 (m, 1H), 3.31(dd, J=9.2, 4.0, 1H), 3.69 (s, 3H), 3.72 (q, J=6.6, 1H), 7.17-7.22 (m,2H), 7.42-7.47 (m, 2H). The configuration of each diastereoisomers wasattributed by comparing the ¹H NMR spectra with published ¹H NMR data ofclose analogues (see R. Almansa, D. Guijarro and M. Yus Tetrahedron:Asymmetry 18, 2007, 2828-2840).

Intermediate 89.3:(R)-1-(S)-1-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-pyrrolidine-2-carboxylicacid methyl ester

The title compound (TFA salt, 50.3 mg, 0.073 mmol, 36%) was obtained asa yellow solid from Intermediate 75.6 (70 mg, 0.20 mmol) andIntermediate 89.1 (95 mg, 0.30 mmol) analogously to Example 75.Purification of the crude material was performed by reverse phaseprep-HPLC (Waters system). HPLC: ^(A)t_(Ret)=1.85 min; LC-MS: m/z 577.5[M+H]⁺.

Intermediate 89.4:(R)-1-(S)-1-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-pyrrolidine-2-carboxylicacid

A mixture of Intermediate 89.3 (TFA salt, 50.3 mg, 0.073 mmol) and LiOHmonohydrate (22 mg, 0.52 mmol) in MeOH (1 ml) and water (0.25 ml) washeated at 60° C. and stirred for 14 h then cooled to RT and directlysubjected to purification by reverse phase prep-HPLC (Waters system) toyield the title compound (TFA salt, 12.4 mg, 0.018 mmol, 25%) as anoff-white solid. HPLC: ^(A)t_(Ret)=1.85 min; LC-MS: m/z 563.6 [M+H]⁺.

Example 90(S)-1-((S)-1-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-pyrrolidine-2-carboxylicacid methyl ester

The title compound (TFA salt, 20.5 mg, 0.030 mmol, 34%) was obtainedfrom Intermediate 75.6 (30 mg, 0.087 mmol) and Intermediate 89.2 (40.6mg, 0.13 mmol) analogously to Example 75. Purification of the crudematerial was performed by reverse phase prep-HPLC (Waters system). HPLC:^(A)t_(Ret)=1.86 min; LC-MS: m/z 577.6 [M+H]⁺.

Example 91

Compounds 91a to 91c were obtained analogously to Example 87 and Example88 by reaction of Intermediate 75.6 with various bromo- or iodo-arylintermediates prepared analogously to Intermediate 87.1 or Intermediate88.3.

# Structure Name/HPLC/MS/NMR 91a

(S)-1-(4-Chloro-phenyl)-2-{4-[(R)-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-ethyl]-phenyl}-7-isopropoxy-6-methoxy- 1,4-dihydro-2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.91; LC-MS: m/z 583.5 [M + H]⁺. 91b

(S)-1-(4-Chloro-phenyl)-2-{4-[1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-cyclopropyl]-phenyl}-7-isopropoxy-6-methoxy-1,4- dihydro-2H-isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.42; LC-MS: m/z 595.6 [M + H]⁺. 91c

(S)-2-{4-[1-(4-Acetyl-piperazin-1-yl)- cyclopropyl]-phenyl}-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4- dihydro-2H-isoquinolin-3-one. HPLC:^(A)t_(Ret) = 1.79; LC-MS: m/z 588.6 [M + H]⁺.

Example 92 Trans-4-dimethylamino-cyclohexanecarboxylic acid{4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methylamide

The title compound (TFA salt, 19.4 mg, 0.027 mmol, 19%) was obtained asa light yellow solid from Intermediate 75.6 (50 mg, 0.145 mmol) andIntermediate 92.2 (58.9 mg, 0.174 mmol) analogously to Example 75.Purification of the crude material was performed by reverse phaseprep-HPLC (Waters system). HPLC: ^(A)t_(Ret)=1.85 min; LC-MS: m/z 604.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 1.01-1.18 (m, 2H), 1.21 (d, J=6.1,3H), 1.25 (d, J=6.1, 3H), 1.39-1.57 (m, 2H), 1.70-1.85 (m, 2H),1.87-2.01 (m, 2H), 2.06-2.22 (m, 1H), 2.61-2.72 (2s, 6H), 3.02-3.21 (m,4H), 3.65 (d, J=19.8, 1H), 3.74 (s, 3H), 3.90 (d, J=19.6, 1H), 4.41-4.50(m, 1H), 6.17 (s, 1H), 6.88 (s, 1H), 7.09 (s, 1H), 7.24-7.42 (m, 8H).

Intermediate 92.1:{4-[(4-Bromo-phenyl)-methyl-carbamoyl]-trans-cyclohexyl}-carbamic acidtert-butyl ester

To a solution of trans-4-(Boc-amino)cyclohexanecarboxylic acid (148 mg,0.608 mmol) in DMF were successively added 4-bromo-N-methylaniline(0.084 ml, 0.669 mmol), Et₃N (0.170 ml, 1.217 mmol) and HATU (278 mg,0.730 mmol) at RT. The reaction mixture was heated at 80° C. for 6 hthen additional HATU (278 mg, 0.730 mmol) was added and the mixture wasfurther stirred at 80° C. for 14 h. The reaction mixture was cooled toRT, diluted with TBME and washed successively with HCl 2M in water andNa₂CO₃ 2M in water. The organic phase was dried over Na₂SO₄, filteredand evaporated to dryness. The resulting crude material was purified byreverse phase prep-HPLC (gradient elution, H₂O containing 0.1% TFA/MeCN8:8→2:8) to yield the title compound (97 mg, 0.236 mmol, 39%) as abrownish solid. HPLC: ^(A)t_(Ret)=2.38 min; LC-MS: m/z 411.4 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆): 0.73-0.99 (m, 2H), 1.35 (s, 9H), 1.32-1.45 (m,3H), 1.55-1.76 (m, 4H), 1.86-2.15 (m, 1H), 3.11 (br. s., 3H), 6.56 (br.s., 1H), 7.27-7.35 (m, 2H), 7.61-7.69 (m, 2H).

Intermediate 92.2: Trans-4-dimethylamino-cyclohexanecarboxylic acid(4-bromo-phenyl)-methyl-amide

The title compound (65 mg, 0.192 mmol, 82%) was obtained as a yellowresin from Intermediate 92.1 (96 mg, 0.233 mmol) analogously toIntermediate 75.8. Purification of the crude material was performed byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, DCM/[DCM/7M NH₃ in MeOH 9:1] 95:5→100% DCM/7M NH₃ in MeOH 9:1).TLC: R_(F)=0.40 (DCM/7M NH₃ in MeOH 9:1); HPLC: ^(A)t_(Ret)=1.23 min;LC-MS: m/z 339.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.70-1.01 (m, 2H),1.31-1.46 (m, 2H), 1.59-1.78 (m, 4H), 1.94-2.19 (m, 8H), 3.11 (br. s.,3H), 7.22-7.38 (m, 2H), 7.57-7.74 (m, 2H).

Example 93(S)-1-(4-Chloro-phenyl)-2-{4-[2-(4-dimethylamino-piperidin-1-yl)-1-methyl-ethyl]-phenyl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (25 mg, 0.042 mmol, 27%) was obtained as a colorlesssolid from Intermediate 75.6 (54 mg, 0.156 mmol) and Intermediate 93.4(61 mg, 0.187 mmol) analogously to Example 75. Purification of the crudematerial was performed by reverse phase prep-HPLC (Waters system). Thepurified compound (TFA salt) was dissolved in MeOH and eluted through abasic ion exchange resin (PL-HCO3 MP SPE from Polymer Laboratories) toremove the TFA salt. HPLC: ^(A)t_(Ret)=1.77 min; LC-MS: m/z 590.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 1.14 (d, J=6.6, 3H), 1.20 (d, J=5.9,3H), 1.24 (d, J=5.9, 3H), 1.27-1.33 (m, 1H), 1.62-1.70 (m, 2H),1.74-2.01 (m, 3H), 2.28-2.35 (m, 2H), 2.79-2.95 (m, 4H), 3.60 (d,J=19.8, 1H), 3.73 (s, 3H), 3.83-3.92 (m, 1H), 4.41-4.51 (m, 1H), 6.08(s, 1H), 6.85 (s, 1H), 7.04-7.12 (m, 3H), 7.16-7.24 (m, 2H), 7.33-7.38(m, 4H).

Intermediate 93.1 2-(4-Bromo-phenyl)-propionic acid ethyl ester

To a solution of ethyl 4-bromophenylacetate (2 g, 8.23 mmol) inanhydrous DMF (20 ml) was carefully added NaH (60% in mineral oil, 0.494g, 12.34 mmol) at 0° C. (ice bath). The resulting slurry was stirred at0° C. for 30 min, then MeI (0.643 ml, 10.28 mmol) was added and thereaction mixture was allowed to warm to RT and further stirred for 1 h.A saturated aqueous NH₄Cl solution was added to quench the reaction andthe mixture was extracted with AcOEt (2×). The combined organicfractions were dried over Na₂SO₄, filtered and evaporated to dryness.The resulting crude material was purified by Combi-Flash Companion™(Isco Inc.) column chromatography (SiO₂; gradient elution, heptane/AcOEt99:1 to 8:2) to yield the title compound (777.8 mg, 3.03 mmol, 37%yield) as a colorless oil. TLC: R_(F)=0.64 (heptane/AcOEt 3:1); HPLC:^(A)t_(Ret)=2.60 min; ¹H NMR (400 MHz, DMSO-d₆): 1.13 (t, J=7.1, 3H),1.37 (d, J=7.1, 3H), 3.79 (q, J=7.1, 1H), 3.98-4.12 (m, 2H), 7.22-7.28(m, 2H), 7.49-7.56 (m, 2H).

Intermediate 93.2 2-(4-Bromo-phenyl)-propionic acid

The title compound (263 mg, 1.15 mmol, 98%) was obtained as a yellowsolid from Intermediate 93.1 (300 mg, 1.17 mmol) analogously toIntermediate 1.2. The crude material was used in the next step withoutfurther purification. HPLC: ^(A)t_(Ret)=1.90 min; ¹H NMR (400 MHz,DMSO-d₆): 1.34 (d, J=7.1, 3H), 3.69 (q, J=7.1, 1H), 7.21-7.28 (m, 2H),7.48-7.55 (m, 2H), 12.42 (s, 1H).

Intermediate 93.32-(4-Bromo-phenyl)-1-(4-dimethylamino-piperidin-1-yl)-propan-1-one

The title compound (370 mg, 1.09 mmol, 96%) was obtained as a yellowresin from Intermediate 93.2 (259 mg, 1.13 mmol) and4-(dimethylamino)-piperidine (174 mg, 1.36 mmol) analogously toIntermediate 92.1. Purification of the crude material was performed byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, DCM/7M NH₃ in MeOH 99:1→9:1). TLC: R_(F)=0.49 (DCM/7M NH₃ inMeOH 9:1); HPLC: ^(A)t_(Ret)=1.28 min; LC-MS: m/z 339.1 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆): 0.26-1.05 (m, 1H), 1.14-1.37 (m, 4H), 1.38-1.77 (m,2H), 2.04 (s, 3H), 2.18 (s, 3H), 2.22-2.38 (m, 1H), 2.52-2.59 (m, 1H),2.61-3.00 (m, 1H), 3.80-3.99 (m, 1H), 4.07-4.19 (m, 1H), 4.30-4.46 (m,1H), 7.17-7.28 (m, 2H), 7.47-7.56 (m, 2H).

Intermediate 93.4{1-[2-(4-Bromo-phenyl)-propyl]-piperidin-4-yl}-dimethyl-amine

To a solution of Intermediate 93.3 (221 mg, 0.651 mmol) in anhydrous THF(3 ml) were successively added BH₃.THF (1M in THF, 3.26 ml, 3.26 mmol)and a few drops of 4M HCl in dioxane at RT. The reaction mixture washeated at 70° C., stirred for 2 h30 then cooled to RT and carefullyquenched by the addition of a 2M aqueous HCl solution (6.5 ml). Themixture was heated at 100° C. and stirred for 30 min, then cooled to RT,diluted with AcOEt and washed with a 2M aqueous Na₂CO₃ solution (2×).The organic phase was dried over Na₂SO₄, filtered and evaporated todryness. The resulting crude material was purified by reverse phasecolumn chromatography (gradient elution, water+0.1% TFA/MeCN+0.1% TFA98:2 to 6:4). Fractions containing the desired compound were collected,basified by the addition of solid Na₂CO₃ and extracted with AcOEt. Theorganic layer was dried over Na₂SO₄, filtered and evaporated to drynessto yield the title compound (127 mg, 0.39 mmol, 60% yield) as acolorless oil which crystallized into a colorless solid on standing.HPLC: ^(A)t_(Ret)=1.10 min; LC-MS: m/z 325.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆): 1.14 (d, J=7.1, 3H), 1.19-1.35 (m, 2H), 1.61-1.70 (m, 2H),1.76-1.91 (m, 2H), 1.92-2.02 (m, 1H), 2.13 (s, 6H), 2.33 (d, J=7.6, 2H), 2.79-2.88 (m, 2H), 2.92 (q, J=7.1, 1H), 7.15-7.23 (m, 2H), 7.41-7.49(m, 2H).

Example 94(S)-1-(4-Chloro-phenyl)-2-{4-[2-(4-dimethylamino-piperidin-1-yl)-1-methyl-2-oxo-ethyl]-phenyl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (TFA salt, 11.6 mg, 0.019 mmol, 13%) was obtained asa light yellow solid from Intermediate 75.6 (50 mg, 0.145 mmol) andIntermediate 93.3 (58.9 mg, 0.174 mmol) analogously to Example 75.Purification of the crude material was performed by reverse phaseprep-HPLC (Waters system). HPLC: ^(A)t_(Ret)=1.91 min; LC-MS: m/z 604.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 1.14-1.32 (m, 10H), 1.37-2.03 (m,3H), 2.41-2.62 (m, 3H), 2.62-3.04 (m, 4H), 3.25-3.39 (m, 1H), 3.60 (d,J=19.8, 1H), 3.73 (s, 3H), 3.81-3.89 (m, 1H), 3.96-4.20 (m, 2H),4.40-4.50 (m, 1H), 4.51-4.61 (m, 1H), 6.05-6.12 (m, 1H), 6.86 (s, 1H),7.03-7.18 (m, 3H), 7.19-7.30 (m, 2H), 7.30-7.42 (m, 4H).

Examples 95, 101, 104, 105, 106, 107, 112, 117, 118, 119, 126, 130, 132,138, 139, 144, 147, 149, 150, 152, 153, 172, 174, 175, 180, 183, 195,196, 197, 198, 199, 200, 202, 203, 204, 205, 207, 209, 210, 211, 212,214, 216, 226, 227, 228 and Intermediates 123.1, 137.1, 163.1, 164.2,169.1, 176.2, 177.2, 178.1, 192.2, 201.1, 215.2, 219.1 were obtainedanalogously to Example 75 by reaction of Intermediate 75.6 (or analoguesprepared similarly).

Examples 96, 98, 182, 188 and Intermediates 166.2, 185.2, 186.1, 187.2,189.3 were obtained analogously to Example 1 by reaction of intermediate96.1 (or analogues prepared similarly).

Structure Name/HPLC/MS 95

(S)-1-(4-Chloro-phenyl)-2-(4-imidazol-1-ylmethyl-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(E)t_(Ret) = 4.686; LC-MS: m/z 502.4 [M + H]⁺. 96

1-(4-Chloro-3-fluoro-phenyl)-2-(4-dimethylamino-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(K)t_(Ret) = 6.166; LC-MS: m/z 483.4 [M + H]⁺. 98

N-{4-[1-((4-Chloro-phenyl)-7-isopropoxy-6-meth-oxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-2,2,2-trifluoro-N-methyl-acetamide. HPLC: ^(K)t_(Ret) = 7.338;LC-MS: m/z 547.1 [M + H]⁺. 99

1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-methylamino-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(K)t_(Ret) = 5.878; LC-MS: m/z 451.4 [M + H]⁺. 100

(S)-1-(4-Chloro-phenyl)-2-(4-{[4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-trans-cyclohexylmethyl]-methyl-amino}-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(A)t_(Ret) = 2.02; LC-MS: m/z 680.2 [M + H]⁺. 101

{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-methoxy-phenyl}-methyl-amino)-methyl]-trans- cyclohexyl}-carbamic acidtert-butyl ester. HPLC: ^(A)t_(Ret) = 2.84; LC-MS: m/z 692.2 [M + H]⁺.102

{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-1,4-dihydro-1H-isoquinolin-2-yl]-3-methoxy-phenyl}-methyl-amino)-methyl]-trans- cyclohexylamino}-aceticacid methyl ester. HPLC: ^(A)t_(Ret) = 1.99; LC-MS: m/z 664.3 [M + H]⁺.103

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(2-methoxy-4-{methyl-[4-(3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.91; LC-MS: m/z 675.3[M + H]⁺. 104

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-[4-(methyl-piperidin-4-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.94;LC-MS: m/z 548.2 [M + H]⁺. 105

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) = 1.164; LC-MS: m/z645.5 [M + H]⁺. 106

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(E)t_(Ret) = 4.57; LC-MS: m/z 659.2[M + H]⁺. 107

4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexanecarboxylic acid methylester. HPLC: ^(G)t_(Ret) = 7.244; LC-MS: m/z 605.4 [M + H]⁺. 108

4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexanecarboxylic acid. HPLC:^(G)t_(Ret) = 6.443; LC-MS: m/z 591.4 [M + H]⁺. 109

4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexanecarboxylic acidmethylamide. HPLC: ^(A)t_(Ret) = 2.12; LC-MS: m/z 604.2 [M + H]⁺. 110

4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexanecarboxylic acid amide.HPLC: ^(A)t_(Ret) = 2.03; LC-MS: m/z 590.2 [M + H]⁺. 111

4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexane-carboxylic acid(2-hydroxy- ethyl)-amide. HPLC: ^(A)t_(Ret) = 1.98; LC-MS: m/z 634.2[M + H]⁺. 112

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[methyl-(4-piperazin-1-yl-trans-cyclohexy- methyl)-amino]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.76;LC-MS: m/z 631.3 [M + H]⁺. 113

(S)-2-(4-{[4-(4-Acetyl-piperazin-1-yl)-trans-cyclohexylmethyl]-methyl-amino}-phenyl)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4- dihydro-2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.89; LC-MS: m/z 673.3 [M + H]⁺. 114

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-2-(4-{[4-(4-methanesulfonyl-piperazin-1-yl)-trans-cyclohexylmethyl]-methyl-amino}-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.97;LC-MS: m/z 709.4 [M + H]⁺. 115

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(A)t_(Ret) = 1.78; LC-MS m/z 645.5 [M + H]⁺. 116

2-{4-[({4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-methyl-acetamide. HPLC: ^(A)t_(Ret) = 1.86; LC-MS:m/z 633.2 [M + H]⁺. 117

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-[4-(methyl-piperidin-2-ylmethyl-amino)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 1.93;LC-MS: m/z 548.4 [M + H]⁺. 118

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6- methoxy-2-{4-[methyl-(tetrahydro-pyran-2-yl-methyl)-amino]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.41;LC-MS: m/z 549.4 [M + H]⁺. 119

(S)-1-(4-Chloro-phenyl)-2-[4-(cyclohexylmethyl-methyl-amino)-phenyl]-7-isopropoxy-6-6methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(A)t_(Ret) = 2.70;LC-MS: m/z 547.5 [M + H]⁺. 120

(S)-2-{5-[(Trans-4-amino-cyclohexylmethyl)-methyl-amino]-pyridin-2-yl}-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one. HPLC:^(F)t_(Ret) = 0.98; LC-MS: m/z 563.4 [M + H]⁺. 121

{4-[({6-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans- cyclohexylamino}-acetic acidmethyl ester. HPLC: ^(F)t_(Ret) = 1.204; LC-MS: m/z 635.5 [M + H]⁺. 122

2-{4-[({6-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-methyl-acetamide. HPLC: ^(F)t_(Ret) = 1.080; LC-MS:m/z 634.2 [M + H]⁺. 123

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) = 1.082; LC-MS: m/z646.2 [M + H]⁺. 124

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(3-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) = 1.236; LC-MS: m/z646.4 [M + H]⁺. 125

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) = 1.019; LC-MS: m/z660.4 [M + H]⁺. 126

{4-[({5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-2-yl}-methyl-amino)-methyl]-trans- cyclohexylamino}-acetice acidmethyl ester. HPLC: ^(G)t_(Ret) = 5.334; LC-MS: m/z 635.4 [M + H]⁺. 127

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 5.162; LC-MS: m/z646.2 [M + H]⁺. 128

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 0.99; LC-MS: m/z 632.2[M + H]⁺. 129

(S)-1-(4-Chloro-phenyl)-2-(6-{[4-(3-hydroxy- methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-methyl-amino}-pyridin-3-yl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 1.01;LC-MS: m/z 662.5 [M + H]⁺. 130

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 5.252; LC-MS: m/z660.5 [M + H]⁺. 131

2-{4-[({5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-2-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-isopropyl-acetamide. HPLC: ^(H)t_(Ret) = 1.21; LX-MA:m/ 662.3 [M + H]⁺. 132

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 5.269; LC-MS: m/z646.5 [M + H]⁺. 133

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-2-(6-{[4-(3-isopropyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-methyl-amino}-pyridin-3-yl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(H)t_(Ret) = 1.40;LC-MS: m/z 674.2 [M + H]⁺. 134

(S)-1-(4-Chloro-phenyl)-3-(6-{[4-(3-ethyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-methyl.amino}-pyridin-3-yl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinoline-3-one. HPLC: ^(G)t_(Ret) = 5.343;LC-MS: m/z 660.3 [M + H]⁺. 135

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl))-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(H)t_(Ret) = 1.54; LC-MS: m/z 646.3 [M + H]⁺. 136

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(2-oxo-piperazin-1-yl)-cis-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(H)t_(Ret) = 1.52; LC-MS: m/z 645.3 [M + H]⁺. 137

(S)-2-{5-[(Trans-4-amino-cyclo- hexylmethyl)-amino]-pyridin-2-yl}-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) = 0.937;LC-MS: m/z 549.4 [M + H]⁺. 138

1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(E)t_(Ret) = 4.737; LC-MS: m/z659.2 [M + H]⁺. 139

{4-[({5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl}-methyl-amino)-methyl]-trans- cyclohexylamino}-acetic acidmethyl ester. HPLC: ^(I)t_(Ret) = 5.36; LC-MS: m/z 636.5 [M + ]⁺. 140

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-methoxy-2-(5-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) =5.167; LC-MS: m/z 661.5 [M + H]⁺. 141

2-{4-[({6-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-ethyl-acetamide. HPLC: ^(F)t_(Ret) = 1.016; LC-MS:m/z 648.5 [M + H]⁺. 142

2-{4-[({6-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-isopropyl-acetamide. HPLC: ^(F)t_(Ret) = 1.035;LC-MS: m/z 662.5 [M + H]⁺. 143

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(2-oxo-azetidin-1-yl)-trans-cyclohexyl-methyl]-amino}-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) = 1.294; LC-MS: m/z617.4 [M + H]⁺. 144

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridazin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 4.465; LC-MS:m/z 661.5 [M + H]⁺. 145

2-{4-[({5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl}-methyl-amino)-methyl]-trans-cyclohexyl-amino}-N-methyl-acetamide. HPLC: ^(I)t_(Ret) = 5.14; LC-MS:m/z 635.5 [M + H]⁺. 146

(S)-1-(4-Chloro-phenyl)-2-(5-{[4-(3-ethyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-methyl-amino}-pyridin-2-yl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) = 1.132;LC-MS: m/z 660.3 [M + H]⁺. 147

(S)-1-(4-Chloro-phenyl)-2-{6-[(3-hydroxy-cyclobutylmethyl)-methyl-amino]-pyridin-3-yl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(F)t_(Ret) = 0.989; LC-MS: m/z 536.4 [M + H]⁺. 148

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-2-(5-{[4-(3-isopropyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexyl-methyl]-methyl-amino}-pyridin-2-yl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) = 1.165;LC-MS: m/z 674.3 [M + H]⁺. 149

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 5.202; LC-MS: m/z647.2 [M + H]⁺. 150

{4-[({2-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrimidin-5-yl}-methyl-amino)-methyl]-trans- cyclohexylamino}-aceticacid methyl ester. HPLC: ^(I)t_(Ret) = 5.07; LC-MS: m/z 636.4 [M + H]⁺.151

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(2,2,2-trifluoro-ethoxy)-1,4- dihydro-2H-isoquinolin-3-one.HPLC: ^(J)t_(Ret) = 6.02; LC-MS: m/z 505.4 [M + H]⁺. 152

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(4-methyl-3-oxo-ipiperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrimidin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 4.929;LC-MS: m/z 661.5 [M + H]⁺. 153

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridazin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 4.497;LC-MS: m/z 647 [M + H]⁺. 154

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(2-methoxyethoxy)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(I)t_(Ret) = 4.577; LC-MS: m/z 481.4 [M + H]⁺. 155

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-[(S)-1-(tetrahydro-furan-2-yl)-methoxy]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 4.72;LC-MS: m/z 507.1 [M + H]⁺. 156

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-[(R)-1-(tetrahydro-furan-2-yl)methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 4.737;LC-MS: m/z 507.3 [M + H]⁺. 157

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-((R)-1-methoxy-propopxy)-1,4- dihydro-2H-isoquinolin-3-one.HPLC: ^(J)t_(Ret) = 5.340; LC-MS: m/z 495.3 [M + H]⁺. 158

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(-2-methoxy-1-methyl-ethoxy))-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(J)t_(Ret) = 5.11; LC-MS: m/z495.2 [M + H]⁺. 159

4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexane-carboxylic acid(2-hydroxy-2- methyl-propyl)-amide. HPLC: ^(G)t_(Ret) = 6.496; LC-MS:m/z 662.5 [M + H]⁺. 160

(4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexane-carboxylic acid((1R,2S) 2-hydroxy- cyclopentyl)-amide. HPLC: ^(G)t_(Ret) = 6.420;LC-MS: m/z 674.6 [M + H]⁺. 161

(4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexane-carboxylic acid ((1R)2-hydroxy- propyl)-amide. HPLC: ^(G)t_(Ret) = 6.305; LC-MS: m/z 648.2[M + H]⁺. 162

(4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans- cyclohexanecarboxylic acid ((S)2-hydroxy- propyl)-amide. HPLC: ^(G)t_(Ret) = 6.111; LC-MS: m/z 648.2[M + H]⁺. 163

1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(C)t_(Ret) = 8.718; LC-MS: m/z 645.2 [M + H]⁺. 164

(S)-2-[4-(3-Amino-1H-pyrazol-4-yl)-phenyl]-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 6.802; LC-MS: m/z503.4 [M + H]⁺. 165

(S)-2-[4-(3-Amino-5-methyl-1H-pyrazol-4-yl)-phenyl]-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 6.662;LC-MS: m/z 517.4 [M + H]⁺. 166

1-(4-Chloro-phenyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(E)t_(Ret) = 4.823; LC-MS: m/z516.3 [M + H]⁺. 167

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-7-(1-hydroxy-cyclopropylmethoxy))-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(J)t_(Ret) = 4.795;LC-MS: m/z 493.4 [M + H]⁺. 168

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(3-methoxy-propoxy)-1,4- dihydro-2H-isoquinolin-3-one. HPLC:^(J)t_(Ret) = 5.417; LC-MS: m/z 495.4 [M + H]⁺. 169

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[1-(2-oxo-piperazin-1-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) = 0.928;LC-MS: m/z 550.0 [M + H]⁺. 170

1-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(oxetan-2-ylmethoxy)-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(J)t_(Ret) = 4.968; LC-MS: m/z 493.4 [M + H]⁺. 171

1-(4-Chloro-phenyl)-7-(2,2-difluoro-ethoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro- 2H-isoquinolin-3-one. HPLC:^(J)t_(Ret) = 5.59; LC-MS: m/z 487.4 [M + H]⁺. 172

{4-[({5-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl}-methyl-amino)-methyl]-trans- cyclohexylamino}-acetic acidmethylester. HPLC: ^(I)t_(Ret) = 5.31; LC-MS: m/z 636.5 [M + H]⁺. 173

2-{4-[({5-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl}-methyl-amino)-methyl]-trans-cyclhexylamino}-N-methyl-acetamide. HPLC: ^(I)t_(Ret) = 5.15; LC-MS: m/z635.6 [M + H]⁺. 174

1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 5.18; LC-MS:m/z 647.5 [M + H]⁺. 175

1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 4.41; LC-MS: m/z660.7 [M + H]⁺. 176

(S)-1-(4-Chloro-phenyl)-2-(3-fluoro-4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 6.588;LC-MS: m/z 677.6 [M + H]⁺. 177

(S)-1-(4-Chloro-phenyl)-2-(2-fluoro-4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 6.766;LC-MS: m/z 677.7 [M + H]⁺. 178

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[(S)-1-(2-oxo-piperazin-1-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(E)t_(Ret) = 4.449 min;LC-MS: m/z 549.2 [M + H]⁺. 179

(S)-1-(4-Chloro-phenyl)-2-(4-{(S)-1-[4-(2-hydroxy-ethyl)-2-oxo-piperazin-1-yl]-ethyl}-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(F)t_(Ret) = 1.080; LC-MS: m/z 634.2 [M + H]⁺. 180

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[(R)-1-(2-oxo-piperazin-1-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) = 0.922; LC-MS: m/z548.5 [M + H]⁺. 181

(S)-1-(4-Chloro-phenyl)-2-(4-{(R)-1-[4-(2-hydroxy-ethyl)-2-oxo-piperazin-1-yl]-ethyl}-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(F)t_(Ret) = 0.932; LC-MS: m/z 592.5 [M + H]⁺. 182

1-(4-Chloro-2-fluoro-phenyl)-2-(4-dimethylamino-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(K)t_(Ret) = 6.178; LC-MS: m/z 483.4 [M + H]⁺. 183

(S)-1-(4-chloro-phenyl)-2-{4-[(3-hydroxy-3-hydroxymethyl-cyclobutylmethyl)-methyl-amino]-phenyl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(F)t_(Ret) = 1.098; LC-MS: m/z 565.5 [M + H]⁺. 184

2-[4-(3-Amino-5-isobutyl-1H-pyrazol-4-yl)-phenyl]-1-(4-chloro-phenyl)-7-isopropoxy-6-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 6.832;LC-MS: m/z 559.5 [M + H]⁺. 185

1-(4-Chloro-phenyl)-2-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-pyridin-3-yl]-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(E)t_(Ret) = 4.685;LC-MS: m/z 517.0 [M + H]⁺. 186

1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(2-methoxy-4-methyl-2-phenyl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(L)t_(Ret) = 5.74; LC-MS: m/z 466.4 [M + H]⁺. 187

1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-[4-methyl-2-(2H-tetrazol-5-ylmethoxy)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(L)t_(Ret) = 5.20; LC-MS: m/z534.4 [M + H]⁺. 188

1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-[4-methyl-2-(thiazol-5-ylmethoxy)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(M)t_(Ret) = 1.23; LC-MS: m/z 549.4[M + H]⁺. 189

4-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-(2H-tetrazol-5-ylmethoxy)-benzoic acid methyl ester. HPLC: ^(M)t_(Ret) =1.10; LC-MS: m/z 578.2 [M + H]⁺. 190

4-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3- methoxy-benzoic acidmethylester. HPLC: ^(M)t_(Ret) = 1.19; LC-MS: m/z 510.3 [M + H]⁺. 191

4-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3- (thiazol-5-ylmethoxy)-benzoicacid methylester. HPLC: ^(M)t_(Ret) = 1.15; LC-MS: m/z 593.3 [M + H]⁺.192

N-((S)-1-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-acetamide. HPLC: ^(K)t_(Ret) = 6.55;LC-MS: m/z 524.5 [M + NH₃]⁺. 193

N-((S)-1-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-2- methoxy-acetamide. HPLC: ^(K)t_(Ret)= 6.72; LC-MS: m/z 554.5 [M + NH₃]⁺. 194

N-((S)-1-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-2- dimethylamino-acetamide. HPLC:^(K)t_(Ret) = 6.15; LC-MS: m/z 550.5 [M + H]⁺. 195

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(2-oxo-pyrrolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(J)t_(Ret) = 4.21; LC-MS: m/z 631.6[M + H]⁺. 196

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(2-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(J)t_(Ret) = 4.60; LC-MS: m/z 632.6[M + H]⁺. 197

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(3-oxo-morpholin-4-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(J)t_(Ret) = 4.72; LC-MS: m/z 647.6[M + H]⁺. 198

(S)-2-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(I)t_(Ret) = 5.475; LC-MS: m/z 661.6 [M + H]⁺. 199

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6- methoxy-2-(6-{methyl-[4-(2-oxo-piperidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(J)t_(Ret) = 4.97; LC-MS: m/z 645.6[M + H]⁺. 200

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[(S)-1-(4-methyl-3-oxo- piperazin-1-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(K)t_(Ret) = 6.01;LC-MS: m/z 562.5 [M + H]⁺. 201

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{6-[(S)-1-(2-oxo-piperazin-1-yl)-ethyl]-pyridin-3-yl}-1,4-dihydro-2H-isoquinoline-3-one. HPLC: ^(E)t_(Ret) =4.515; LC-MS: m/z 549.2 [M + H]⁺. 202

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[(S)-1-(2-oxo-tetrahydro-pyrimidin-1-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(F)t_(Ret) =1.178; LC-MS: m/z 565.4 [M + NH₃]⁺. 203

(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(I)t_(Ret) = 4.671; LC-MS: m/z 660.6 [M + H]⁺. 204

(S)-1-(4-Chloro.phenyl)-7-cyclobutoxy-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(I)t_(Ret) = 4.52; LC-MS: m/z 658.6 [M + H]⁺. 205

(S)-1-(4-Chloro-phenyl)-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-7-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(I)t_(Ret) = 4.26; LC-MS: m/z 688.7 [M + H]⁺. 206

1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(K)t_(Ret) = 6.81; LC-MS: m/z 505.4 [M + H]⁺. 207

(S)-1-(4-Chloro-phenyl)-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-7-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(E)t_(Ret) = 4.686; LC-MS: m/z 689.7 [M + H]⁺. 208

1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(E)t_(Ret) = 5.090; LC-MS: m/z 506.0 [M + H]⁺. 209

(S)-1-(4-Chloro-phenyl)-7-cyclobutoxy-6- methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) =5.31; LC-MS: m/z 659.6 [M + H]⁺. 210

(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) =4.64; LC-MS: m/z 674.7 [M + H]⁺. 211

(S)-1-(4-Chloro-phenyl)-7-cyclobutoxy-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) =4.52; LC-MS: m/z 672.7 [M + H]⁺. 212

(S)-1-(4-Chloro-phenyl)-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-7-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(E)t_(Ret) = 4.10; LC-MS: m/z 702.0 [M + H]⁺. 213

2-[4-(3-Amino-5-ethyl-1H-pyrazol-4-yl)-phenyl]-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(G)t_(Ret) = 7.089; LC-MS: m/z531.5 [M + H]⁺. 214

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[(S)-1-(3-oxo-morpholin-4-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(E)t_(Ret) = 5.253;LC-MS: m/z 549 [M + H]⁺. 216

(S)-1-(4-Chloro-phenyl)-2-(2-fluoro-6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(G)t_(Ret) = 6.661; LC-MS m/z 678.3 [M + H]⁺. 217

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-2-{4-[(S)-1-(4-methanesulfonyl-2-oxo-piperazin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(E)t_(Ret) = 5.131; LC-MS: m/z 626.2 [M + H]⁺. 218

(S)-2-{4-[(S)-1-(4-Acetyl-2-oxo-piperazin-1-yl)-ethyl]-phenyl}-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(E)t_(Ret) = 5.126;LC-MS: m/z 590.2 [M + H]⁺. 219

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{6-[(R)-1-(2-oxo-piperazin-1-yl)-ethyl]-pyridin-3-yl}-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(E)t_(Ret) = 4.449;LC-MS: m/z 549.2 [M + H]⁺. 220

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{(S)-1-[2-oxo-4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-ethyl}-phenyl)-1,4-dihydro- 2H-isoquinolin-3-one.HPLC: ^(E)t_(Ret) = 4.762; LC-MS: m/z 632.2 [M + H]⁺. 221

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-2-{4-[(S)-1-(4-isopropyl-2-oxo-piperazin-1-yl)-ethyl]-phenyl}-6-methoxy-1,4-dihydro-2H-isoquinolin- 3-one. HPLC: ^(E)t_(Ret) =4.831; LC-MS: m/z 590.3 [M + H]⁺. 222

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[(S)-1-(4-methyl-2-oxo-piperazin-1-yl)-ethyl]-phenyl}-1,4-dihydro-2H- isoquinolin-3-one. HPLC:^(E)t_(Ret) = 4.711; LC-MS: m/z 562.3 [M + H]⁺. 223

1-(4-Chloro-phenyl)-6-hydroxy-7-isopropoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(J)t_(Ret) = 3.99; LC-MS:m/z 632.6 [M + H]⁺. 224

(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-hydroxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(J)t_(Ret) = 4.11min; LC-MS: m/z 660.7 [M + H]⁺. 225

1-(4-Chloro-phenyl)-6-hydroxy-7-isopropoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 4.10; LC-MS:m/z 646.6 [M + H]⁺. 226

1-(4-Chloro-phenyl)-7-isopropoxy-6-d₃-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 4.38 min; LC-MS:m/z 663.6 [M + H]⁺. 227

1-(4-Chloro-phenyl)-7-isopropoxy-6-d₃-methoxy-2-(6-{d₃-methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one. HPLC: ^(I)t_(Ret) = 4.38; LC-MS:m/z 666.6 [M + H]⁺. 228

(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{d₃-methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin- 3-one. HPLC: ^(I)t_(Ret) =4.38; LC-MS: m/z 663.6 [M + H]⁺.

Intermediate 95.1: 1-(4-Iodo-benzyl)-1H-imidazole

To a solution of imidazole (400 mg, 5.88 mmol) and K₂CO₃ (1.22 g, 8.81mmol) in DMF (19 ml) was added 4-iodobenzyl bromide (1.83 g, 6.17 mol)at RT under protection from light. After stirring for 11.5 h, thereaction mixture was poured into water. The aqueous layer was extractedtwice with EtOAc, the combined organic layers were washed with water andbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography to afford the title compound (757 mg,2.66 mmol, 45%) as a beige solid. HPLC: ^(E)t_(Ret)=3.838 min; LC-MS:m/z 285.2 [M+H]⁺.

Intermediate 96.1: (4-Isopropoxy-3-methoxy-phenyl)-acetyl chloride

To a solution of Intermediate 96.2 (1.41 g, 6.29 mmol) in DCM (50 mL)was added 1-chloro-N,N,2-trimethylpropenylamine (1.0 mL, 7.55 mol) at 0°C. After stirring for 0.5 h, the reaction mixture was concentrated invacuo and the crude product was used without further purification. HPLC:^(E)t_(Ret)=4.772 min (Methyl ester after quenching by MeOH).

Intermediate 96.2: (4-Isopropoxy-3-methoxy-phenyl)-acetic acid

The title compound (11.5 g, 78 mmol, 99%) was obtained as a white solidfrom Intermediate 75.1 (20.0 g, 79 mmol) analogously to Intermediate1.2. HPLC: ^(E)t_(Ret)=4.117 min; LC-MS: m/z 223 [M+H]⁻.

Example 98N-{4-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-2,2,2-trifluoro-N-methyl-acetamide

The title compound (236 mg, 0.43 mmol, 53.1%) was obtained as a whitesolid from Intermediate 98.1 (410 mg, 0.81 mmol) and 2-iodopropane (0.24mL, 2.43 mmol) analogously to Intermediate 138.2. HPLC: ^(K)t_(Ret)=7.34min; LC-MS: m/z 547.2 [M+H]⁺.

Intermediate 98.1:N-{4-[1-(4-Chloro-phenyl)-7-hydroxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-2,2,2-trifluoro-N-methyl-acetamide

The title intermediate (415 mg, 0.82 mmol, 57.8%) was obtained as awhite solid from Intermediate 98.2 (629 mg, 1.84 mmol) and Intermediate187.3 (723 mg, 1.42 mmol) analogously to Example 1. The4-methoxyphenylmethyl group was cleaved in-situ under the reactionconditions. HPLC: ^(K)t_(Ret)=6.478 min; LC-MS: m/z 505.1 [M+H]⁺.

Intermediate 98.2:N-(4-{[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-amino}-phenyl)-2,2,2-trifluoro-N-methyl-acetamide

The title compound (0.73 g, 2.16 mmol, 47.1%) was obtained as a whitesolid from Intermediate 98.3 (1.0 g, 4.58 mmol) and4-chloro-benzaldehyde (0.71 g, 5.04 mmol) analogously to Intermediate1.4. ¹H NMR (600 MHz, DMSO-d₆) 3.30 (s, 3H) 7.35 (d, 2H) 7.49 (d, 2H)7.61 (d, 2H) 7.96 (d, 2H) 8.67 (s, 1H).

Intermediate 98.3: N-(4-Amino-phenyl)-2,2,2-trifluoro-N-methyl-acetamide

The title intermediate (2.67 g, 12.2 mmol, 100%) was obtained as a solidfrom Intermediate 98.4 (3.0 g, 12.1 mmol) analogously to Intermediate43.2. HPLC: ^(K)t_(Ret)=0.73 min; LC-MS: m/z 219.3 [M+H]⁺.

Intermediate 98.4: 2,2,2-Trifluoro-N-methyl-N-(4-nitro-phenyl)-acetamide

The title intermediate (11.8 g, 12.2 mmol, 100%) was obtained as a solidfrom N-methyl-4-nitroaniline (8.5 g, 54.2 mmol) and trifluoroaceticanhydride (11.4 mL, 81 mmol) analogously to Intermediate 43.1. HPLC:^(K)t_(Ret)=1.90 min; LC-MS: m/z 249.4 [M+H]⁺.

Example 100(S)-1-(4-Chloro-phenyl)-2-(4-{[4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-trans-cyclohexylmethyl]-methyl-amino}-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (25 mg, 0.031 mmol, 59%) was obtained as a whitesolid from Intermediate 77.3 (30 mg, 0.053 mmol) and divinylsulfone (6.3mg, 0.053 mmol) analogously to Intermediate 87.1. HPLC: ^(A)t_(Ret)=2.02min; LC-MS: m/z 680.2 [M+H]⁺.

Intermediate 101.1:(4-{[(4-Bromo-3-methoxy-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

The title intermediate (266 mg, 0.62 mmol, 49%) was obtained as a whitesolid from Intermediate 101.2 (695 mg, 1.86 mmol) and 37% water solutionof formaldehyde (0.38 mL, 5.08 mmol) analogously to Intermediate 77.1.HPLC: ^(A)t_(Ret)=2.67 min; LC-MS: m/z 427.1 [M+H]⁺.

Intermediate 101.2:{4-[(4-Bromo-3-methoxy-phenylamino)-methyl]-trans-cyclohexyl}-carbamicacid tert-butyl ester

The title intermediate (526 mg, 1.27 mmol, 86%) was obtained as a greysolid from (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (371 mg,1.63 mmol) and 4-bromo-3-methoxyaniline (300 mg, 1.48 mmol) analogouslyto Intermediate 75.7. HPLC: ^(A)t_(Ret)=2.60 min; LC-MS: m/z 413.1[M+H]⁺.

Intermediate 102.1:(S)-2-{4-[(Trans-4-amino-cyclohexylmethyl)-methyl-amino]-2-methoxy-phenyl}-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (40.9 mg, 0.058 mmol, 100%) was obtained as aorange resin from Example 101 (40 mg, 0.58 mmol) analogously to Example51. HPLC: ^(A)t_(Ret)=1.90 min; LC-MS: m/z 592.2 [M+H]⁺.

Intermediate 103.1:((2-tert-Butoxycarbonylamino-ethyl)-{-[({4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-methoxy-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

The title intermediate (37 mg, 0.038 mmol, quantitative) was obtained asa yellow solid from Example 102 (25 mg, 0.038 mmol) andN-Boc-2-aminoacetaldehyde (9 mg, 0.056 mmol) analogously to Intermediate79.2. HPLC: ^(A)t_(Ret)=2.31 min; LC-MS: m/z 807.4[M+H]⁺.

Intermediate 104.1: (4-Iodo-phenyl)-methyl-piperidin-4-ylmethyl-amine

The title intermediate (94 mg, 0.28 mmol, 61.2%) was obtained as ayellow resin from Intermediate 104.2 (200 mg, 0.46 mmol) analogously toExample 51. HPLC: ^(A)t_(Ret)=1.50 min; LC-MS: m/z 331.1 [M+H]⁺.

Intermediate 104.2:4-{[(4-Iodo-phenyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acidtert-butyl ester

The title intermediate (3.27 g, 7.60 mmol, 83%) was obtained as a brownoil from Intermediate 104.3 (4.27 g, 9.13 mmol) and 37% water solutionof formaldehyde (1.36 mL, 18.2 mmol) analogously to Intermediate 77.1.HPLC: ^(A)t_(Ret)=3.19 min; LC-MS: m/z 431 [M+H]⁺.

Intermediate 104.3:4-[(4-Iodo-phenylamino)-methyl]-piperidine-1-carboxylic acid

The title intermediate (4.27 g, 9.13 mmol, 100%) was obtained as aviolet solid from 4-formyl-piperidine-1-carboxylic acid tert-butyl ester(2.73 g, 12.8 mmol) and 4-iodoaniline (2.0 g, 9.13 mmol) analogously toIntermediate 75.7. HPLC: ^(A)t_(Ret)=2.97 min; LC-MS: m/z 361.1[M+HCOOH]⁺.

Example 105(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (104 mg, 0.16 mmol, 19.4%) was obtained as a yellowsolid from Intermediate 75.6 (287 mg, 0.83 mmol) and Intermediate 105.1(372 mg, 0.87 mmol) analogously to Example 75. HPLC: ^(F)t_(Ret)=1.164min; LC-MS: m/z 645.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) 0.85-1.09 (m,4H) 1.19 (dd, J=19.55, 5.86 Hz, 6H) 1.49-1.87 (m, 5H) 2.08-2.25 (m, 1H)2.70 (s, 3H) 2.85 (s, 3H) 3.09 (s, 4H) 3.55 (d, J=19.94 Hz, 1H) 3.71 (s,3H) 3.87 (d, J=19.55 Hz, 1H) 4.02 (s, 2H) 4.33-4.49 (m, 1H) 5.92 (s, 1H)6.54 (d, J=8.99 Hz, 2H) 6.80 (s, 1H) 6.87 (d, J=8.99 Hz, 2H) 7.02 (s,1H) 7.33 (s, 4H).

Intermediate 105.1:1-(4-{[(4-Iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl)-3-methyl-imidazolidin-4-one

A mixture of Intermediate 105.2 (535 mg, 1.29 mmol) and 37% aqueoussolution of formaldehyde (0.96 mL, 12.9 mmol) in EtOH (20 mL) was sealedand heated at 80° C. for 20 h. The reaction mixture was concentrated invacuo, then the resulting yellow oil was directly purified by columnchromatography to afford the title compound (553 mg, 1.29 mmol, 100%) asa beige solid. HPLC: ^(F)t_(Ret)=1.088 min; LC-MS: m/z 428.1 [M+H]⁺.

Intermediate 105.2:2-(4-{[(4-Iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexylamino)-N-methyl-acetamide

A mixture of Intermediate 105.3 (700 mg, 1.68 mmol) and 33% EtOHsolution of MeNH₂ (2.1 mL, 168 mmol) was sealed and heated at 80° C. for24 h. The reaction mixture was concentrated in vacuo, then the resultingyellow oil was directly purified by column chromatography to afford thetitle compound (535 mg, 1.29 mmol, 77%) as a beige solid.

HPLC: ^(F)t_(Ret)=0.982 min; LC-MS: m/z 416.2 [M+H]⁺.

Intermediate 105.3:(4-{[(4-Iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexylamino)-aceticacid methyl ester

To a solution of Intermediate 105.4 (16.9 g, 49.2 mmol) in DMF (300 mL)was successively added potassium carbonate (14.3 g, 103 mmol) and methyl2-bromoacetate (4.77 mL, 51.7 mmol) at −10° C. The suspension wasstirred for 4.5 h at −10° C. to 10° C. The reaction mixture was dilutedwith EtOAc, the organic phase was washed with water and brine, and driedover Na₂SO₄, filtered and evaporated to dryness. Purification of theresidue by normal phase column chromatography, eluting with 100% DCM to100% EtOAc, gave the title compound as brown oil (9.45 g, 21.6 mmol,43.8%). HPLC: ^(E)t_(Ret)=4.22 min; LC-MS: m/z 417.0 [M+H]⁺.

Intermediate 105.4:(Trans-4-amino-cyclohexylmethyl)-(4-iodo-phenyl)-methyl-amine

To a solution of Intermediate 77.1 (21.9 g, 49.5 mmol) in DCM (300 mL)was added drop wise TFA (114 mL, 1484 mmol) at 0° C. The reactionmixture was stirred for 30 min at RT, then concentrated in vacuo. Theresidue was diluted with EtOAc, and adjusted to pH 9 at 0° C. byaddition of 2M NaOH. The phases were separated and water layer wasextracted with EtOAc. The organic layer was washed with water and brine,dried over Na₂SO₄, and filtered. Concentration in vacuo gave the titlecompound as grey solid (16.9 g, 47.8 mmol, 97%). HPLC: ^(E)t_(Ret)=3.92min; LC-MS: m/z 345.1 [M+H]⁺.

Example 106(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

A sealable reaction flask was charged with potassium phosphate (4.44 g,20.29 mmol), evacuated and heated for 15 min at 170° C. The reactionflask was back-filled with argon at RT and Intermediate 75.6 (3.64 g,10.15 mmol), Intermediate 106.1 (5.48 g, 12.18 mmol), dioxan (75 mL) and(+/−)-trans-1,2-diaminocyclohexane (0.37 mL, 3.04 mmol) were addedsubsequently. The reaction flask was carefully evacuated under vacuum(2×) and backfilled with argon (2×) and copper (I) iodide (0.586 g, 3.04mmol) were added. The reaction mixture was stirred for 22.5 h at 95° C.The mixture was extracted between EtOAc (3×) and water (3×). The organicphases were washed with brine and dried over Na₂SO₄, filtered andevaporated to dryness. Purification of the residue by normal phasecolumn chromatography, eluting with 100% EtOAc to 20% MeOH/EtOAcfollowed by reverse phase prep-HPLC afforded the TFA salt which wasextracted between EtOAc (2×) and 1M aqueous NaHCO₃ (1×). The organicphases were washed with brine and dried over Na₂SO₄, filtered andevaporated to dryness gave the title compound as white solid (1.59 g,2.41 mmol, 23.8%): HPLC: ^(E)t_(Ret)=4.57 min; LC-MS: m/z 659.2 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) 0.88-1.01 (m, 2H) 1.05-1.14 (m, 2H) 1.16 (d,J=5.86 Hz, 3H) 1.21 (d, J=6.25 Hz, 3H) 1.48-1.62 (m, 1H) 1.73 (dd, 4H)2.14-2.27 (m, 1H) 2.65 (t, J=5.47 Hz, 2H) 2.76 (s, 3H) 2.85 (s, 3H) 3.02(s, 2H) 3.06-3.20 (m, 4H) 3.54 (d, 1H) 3.71 (s, 3H) 3.87 (d, J=19.53 Hz,1H) 4.39-4.47 (m, 1H) 5.92 (s, 1H) 6.54 (d, 2H) 6.81 (s, 1H) 6.87 (d,2H) 7.02 (s, 1H) 7.33 (s, 4H).

Intermediate 106.1:4-(4-{[(4-Iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl)-1-methyl-piperazin-2-one

To a solution of Intermediate 106.2 (13.3 g, 20.9 mmol) in dioxane (52.3mL) was added 4M dioxane solution of HCl (105 mL, 418 mmol) at 0° C. Thereaction mixture was stirred at RT for 0.5 h. The solution wasconcentrated and the residue was dissolved in MeOH (157 mL),triethylamine (27.3 ml, 196 mmol) was added drop wise at 0° C. and themixture was stirred for 1 h at RT. The reaction mixture was concentratedand the residue extracted between EtOAc (2×) and 1M aqueous NaHCO₃ (1×).The organic phases were washed with brine and dried over Mg₂SO₄,filtered and evaporated to dryness. The cure material was suspended inEt₂O (50 mL), and after stirring and sonication during 30 min, it wasfiltered on paper, washed with Et₂O (50 mL) and dryness under highvacuum to give a white powder (8.11 g, 18.0 mmol, 86%). HPLC:^(E)t_(Ret)=4.035 min; LC-MS: m/z 442.1 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) 0.84-1.02 (m, 2H) 1.02-1.12 (m, 2H) 1.52-1.60 (m, 1H) 1.60-1.84(m, 4H) 2.16-2.27 (m, 1H) 2.65 (t, J=5.47 Hz, 2H) 2.76 (s, 3H) 2.85 (s,3H) 3.02 (s, 2H) 3.10 (d, J=7.03 Hz, 2H) 3.14-3.20 (m, 2H) 6.47 (d, 2H)7.37 (d, 2H).

Intermediate 106.2:[[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-(4-{[(4-iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl)-amino]-aceticacid methyl ester

To a suspension of Intermediate 105.3 (9.45 g, 21.6 mmol),methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (4.11 g, 23.7 mmol)and AcOH (3.7 mL, 64.7 mmol) in DCM (108 mL) was added potion wiseNaBH(OAc)₃ (13.7 g, 64.7 mmol) at 0° C. After stirring for 1 h at RT,the reaction mixture was added carefully saturated aqueous NaHCO₃ to pH8 followed by extraction with DCM (2×). The organic phases were driedover Mg₂SO₄, filtered and evaporated, which gave the crude titleintermediate (13.3 g, 20.9 mmol, 97% with 90% purity). This material wasused for the next step without further purifications. HPLC:^(E)t_(Ret)=5.32 min; LC-MS: m/z 574.3 [M+H]⁺.

Example 1074-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexanecarboxylicacid methyl ester

The title compound (244 mg, 0.40 mmol, 25.8%) was obtained as a whitesolid from Intermediate 75.6 (540 mg, 1.56 mmol) and Intermediate 107.1(665 mg, 1.71 mmol) analogously to Example 75. HPLC: ^(G)t_(Ret)=7.244min; LC-MS: m/z 605.4 [M+H]⁺.

Intermediate 107.1:4-{[(4-Iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexanecarboxylicacid methyl ester

The title intermediate (700 mg, 1.81 mmol, 97%) was obtained as a whitesolid from Intermediate 107.2 (695 mg, 1.86 mmol) and 37% water solutionof formaldehyde (306 mg, 3.72 mmol) analogously to Intermediate 77.1.HPLC: ^(G)t_(Ret)=8.063 min; LC-MS: m/z 388.2 [M+H]⁺.

P Intermediate 107.2:4-[(4-Iodo-phenylamino)-methyl]-trans-cyclohexanecarboxylic acid methylester

The title intermediate (700 mg, 1.87 mmol, 40%) was obtained as a whitesolid from 4-formyl-cyclohexanecarboxylic acid methyl ester (800 mg, 4.7mmol) and 4-iodoaniline (601 mg, 2.74 mmol) analogously to Intermediate75.7. HPLC: ^(G)t_(Ret)=7.874 min; LC-MS: m/z 374.2 [M+H]⁺.4-Formyl-cyclohexanecarboxylic acid methyl ester was prepared by thefollowing method. To a solution oftrans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (which isreported in Synthesis Comm. (1982) page 42-43) (861 mg, 5.0 mmol) andEt₃N (2.1 mL, 15.0 mmol) in DCM (16 mL) was slowly added a solution ofpyridine sulfur trioxide (2.39 g, 15 mmol) in DMSO (10 mL) at 0° C. (icebath). After 70 min stirring, it was then diluted into DCM and washedwith water. The organic layer was dried over Na₂SO₄, filtered andevaporated to dryness. This crude material (0.8 g, 4.7 mmol) was usedfor the next step without further purification.

Example 1084-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexanecarboxylicacid

The title compound (81 mg, 0.124 mmol, 100%) was obtained as a whitesolid from Example 107 (75 mg, 0.124 mmol) analogously to Intermediate26.1. HPLC: ^(G)t_(Ret)=6.497 min; LC-MS: m/z 591.2 [M+H]⁺.

Intermediate 112.1:(4-Iodo-phenyl)-methyl-(4-piperazin-1-yl-trans-cyclohexylmethyl)-amine

The title intermediate (351 mg, 0.85 mmol, 74.1%) was obtained as awhite solid from Intermediate 112.2 (650 mg, 1.14 mmol) and analogouslyto Intermediate 88.2. HPLC: ^(A)t_(Ret)=1.32 min; LC-MS: m/z414.1[M+H]⁺.

Intermediate 112.2:(4-Iodo-phenyl)-methyl-{4-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-trans-cyclohexylmethyl}-amine

The title intermediate (654 mg, 1.15 mmol, 54.2%) was obtained as awhite solid from Intermediate 105.4 (0.73 g, 2.12 mmol) andN,N-bis(2-chloroethyl)-4-methylbenzene-sulfonamide (0.73 g, 2.23 mmol)analogously to Intermediate 88.1. HPLC: ^(A)t_(Ret)=2.07 min; LC-MS: m/z568.0 [M+H]⁺.

Example 1162-{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-methyl-acetamide

The title compound (94.9 mg, 0.15 mmol, 95%) was obtained as a yellowsolid from Intermediate 79.1 (100 mg, 0.158 mmol) analogously toIntermediate 105.2. HPLC: ^(A)t_(Ret)=1.86 min; LC-MS: m/z 633.2 [M+H]⁺.

Intermediate 117.1: (4-Iodo-phenyl)-methyl-piperidin-2-ylmethyl-amine

The title intermediate (200 mg, 0.61 mmol, 89%) was obtained as a brownresin from Intermediate 117.2 (308 mg, 0.68 mmol) analogously to Example51. HPLC: ^(A)t_(Ret)=1.49 min; LC-MS: m/z 331.2 [M+H]⁺.

Intermediate 117.2:2-{[(4-Iodo-phenyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acidtert-butyl ester

The title intermediate (310 mg, 0.68 mmol, 100%) was obtained as aviolet solid from 2-formyl-piperidine-1-carboxylic acid tert-butyl ester(213 mg, 0.72 mmol) and 4-iodoaniline (150 mg, 0.68 mmol) analogously toIntermediate 75.7, and successively methylation was performedanalogously to Intermediate 77.1. HPLC: ^(A)t_(Ret)=3.23 min; LC-MS: m/z431.2 [M+H]⁺.

Intermediate 118.1:(4-Iodo-phenyl)-methyl-(tetrahydro-pyran-2-ylmethyl)-amine

The title intermediate (143 mg, 0.43 mmol, 78%) was obtained as lightbrown oil from Intermediate 118.2 (175 mg, 0.55 mmol) and 37% watersolution of formaldehyde (0.12 mL, 1.65 mmol) analogously toIntermediate 77.1. HPLC: ^(A)t_(Ret)=2.48 min; LC-MS: m/z 332.2 [M+H]⁺.

Intermediate 118.2: (4-Iodo-phenyl)-(tetrahydro-pyran-2-ylmethyl)-amine

The title intermediate (177 mg, 0.56 mmol, 13%) was obtained as a brownsolid from 2H-pyran-2-carboxaldehyde (490 mg, 4.29 mmol) and4-iodoaniline (940 mg, 4.29 mmol) analogously to Intermediate 75.7.HPLC: ^(A)t_(Ret)=2.44 min; LC-MS: m/z 318.2 [M+H]⁺.

Intermediate 119.1: Cyclohexylmethyl-(4-iodo-phenyl)-methyl-amine

The title intermediate (195 mg, 0.59 mmol, 86%) was obtained as acolorless oil from cyclohexanecarbaldehyde (81 mg, 0.72 mmol) and4-iodoaniline (150 mg, 0.68 mmol) analogously to Intermediate 75.7, andsuccessively methylation was performed analogously to Intermediate 77.1.HPLC: ^(A)t_(Ret)=3.26 min; LC-MS: m/z 330.2 [M+H]⁺.

Example 120(S)-2-{5-[(Trans-4-amino-cyclohexylmethyl)-methyl-amino]-pyridin-2-yl}-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (334 mg, 0.593 mmol, 78%) was obtained as a yellowfoam from Intermediate 120.1 (504 mg, 0.760 mmol) analogously to Example51: HPLC: ^(F)t_(Ret)=0.98; LC-MS: m/z 563.4 [M+H]⁺.

Intermediate 120.1:{4-[({6-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans-cyclohexyl}-carbamicacid tert-butyl ester

The title intermediate (151 mg, 0.228 mmol, 79%) was obtained as a brownsolid from Intermediate 120.2 (176 mg, 0.347 mmol) and Intermediate 75.6(100 mg, 0.289 mmol) analogously to Example 75. HPLC: ^(F)t_(Ret)=1.563;LC-MS: m/z 663.5 [M+H]⁺.

Intermediate 120.2:(4-{[(6-Iodo-pyridin-3-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

The title intermediate (1.0 g, 2.24 mmol, 64%) was obtained as a solidfrom Intermediate 120.3 (1.5 g, 3.48 mmol) and formaldehyde (37% inwater, 0.326 mL, 4.35 mmol) analogously to Intermediate 77.1. HPLC:^(F)t_(Ret)=1.446; LC-MS: m/z 446.2 [M+H]⁺.

Intermediate 120.3:{4-[(6-Iodo-pyridin-3-ylamino)-methyl]-trans-cyclohexyl}-carbamic acidtert-butyl ester

The title intermediate (1.95 g, 4.52 mmol, 99%) was obtained as a slightpink solid from trans-(4-formylcyclohexyl) carbamic acid tert-butylester (1.136 g, 5 mmol) and 6-Iodo-pyridin-3-ylamine (1 g, 4.55 mmol)analogously to Intermediate 75.7. HPLC: ^(F)t_(Ret)=1.289; LC-MS: m/z432.1 [M+H]⁺.

Example 121{4-[({6-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-aceticacid methyl ester

The title compound (140 mg, 0.221 mmol, 45%) was obtained as a yellowfoam from Example 120 (275 mg, 0.487 mmol) analogously to Intermediate79.1. HPLC: ^(F)t_(Ret)=1.204; LC-MS: m/z 635.5 [M+H]⁺.

Example 1222-{4-[({6-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-methyl-acetamide

The mixture of Example 121 (65 mg, 0.102 mmol) and a solution ofmethylamine (33% in EtOH, 1.2 mL, 10.23 mmol) was heated for 15 h at 90°C. The mixture was concentrated under vacuum and the precipitatecollected by filtration. The residue was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,DCM/[DCM/EtOH 9:1] 1:0→3:7) yielding the title compound as a yellowsolid (40 mg, 0.064 mmol, 63%). HPLC: ^(F)t_(Ret)=1.080; LC-MS: m/z634.2 [M+H]⁺.

Example 123(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 123.1 (44 mg, 0.045 mmol) in MeOH (1 mL)was added HCl (4M in dioxane, 0.564 mL, 2.256 mmol) at RT. The reactionmixture was stirred at RT for 2 h and evaporated to dryness. Theresulting residue was dissolved in MeOH (1 mL) then Et₃N (0.094 mL,0.677 mmol) was added and the mixture was stirred at RT for 1.5 h. Afterevaporation to dryness, the residue was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,DCM/[DCM/EtOH/NH3 aq. 90:9: 1] 1:0→1:9) yielding the title compound as ayellow solid (17 mg, 0.027 mmol, 60%). HPLC: ^(F)t_(Ret)=1.082; LC-MS:m/z 646.2 [M+H]⁺.

Intermediate 123.1:((2-tert-Butoxycarbonylamino-ethyl)-{-4-[({6-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

The title intermediate (44 mg, 0.045 mmol, quantitative) was obtained asa yellow solid from Example 121 (30 mg, 0.048 mmol) analogously toIntermediate 79.2. HPLC: ^(F)t_(Ret)=1.444; LC-MS: m/z 778.6 [M+H]⁺.

Example 124(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one

The mixture of Example 122 (38 mg, 0.061 mmol) and formaldehyde (0.046ml, 37% solution, 10 eq, 0.612 mmol) was heated for 15 h in EtOH (1 mL)at 80° C. The reaction mixture was concentrated to dryness and theresidue was purified by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, DCM/[DCM/MeOH 9: 1] 1:0→0:1)yielding the title compound as a colorless solid (31 mg, 0.048 mmol,79%). HPLC: ^(F)t_(Ret)=1.236; LC-MS: m/z 646.4 [M+H]⁺.

Example 125(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (140 mg, 0.221 mmol, 45%) was obtained as a yellowfoam from Intermediate 125.1 (275 mg, 0.487 mmol) analogously to Example123. HPLC: ^(F)t_(Ret)=1.019; LC-MS: m/z 660.4 [M+H]⁺.

Intermediate 125.1:([2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-{4-[({6-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

The title intermediate (84 mg, 0.107 mmol, 90%) was obtained as a yellowsolid from Example 121 (75 mg, 0.118 mmol) andN-Boc-(methylamino)acetaldehyde (24.54 mg, 0.142 mmol) analogously toIntermediate 79.2. HPLC: ^(F)t_(Ret)=1.256; LC-MS: m/z 792.2 [M+H]⁺.

Example 126{4-[({5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-2-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-aceticacid methyl ester

The title compound (250 mg, 0.39 mmol, 29%) was obtained as a whitesolid from Intermediate 75.6 (470 mg, 1.36 mmol) and Intermediate 130.3(680 mg, 1.63 mmol) analogously to Example 75. HPLC: ^(G)t_(Ret)=5.334min; LC-MS: m/z 635.4 [M+H]⁺.

Intermediate 127.1:((2-tert-Butoxycarbonylamino-ethyl)-{4-[({5-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-2-yl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

The title intermediate (24.6 mg, 0.032 mmol, 41.8%) was obtained as awhite solid from Example 126 (48 mg, 0.076 mmol) andN-Boc-2-aminoacetaldehyde (25.3 mg, 0.151 mmol) analogously toIntermediate 79.2. HPLC: ^(G)t_(Ret)=5.832 min; LC-MS: m/z 778.6 [M+H]⁺.

Example 128(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

A mixture of Intermediate 128.1 (153 mg, 0.23 mmol) and 37% aqueoussolution of formaldehyde (0.17 mL, 2.32 mmol) in EtOH (5 mL) was sealedin a vial and heated for 3.5 h at 80° C. The reaction mixture wasconcentrated in vacuo and the resulting brownish oil was purified bycolumn chromatography respectively preparative thin layer chromatographyto afford the title compound (5 mg, 7.12 mmol, 3%) as a colorless resin.HPLC: ^(G)t_(Ret)=0.99; LC-MS: m/z 632.2 [M+H]⁺. Additionally,Intermediate 129 (44.5 mg, 0.067 mmol, 29%) was identified as a sideproduct and isolated from the crude reaction mixture. HPLC:^(G)t_(Ret)=1.01; LC-MS: m/z 662.5 [M+H]⁺.

Intermediate 128.1:2-{4-[({5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-2-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-acetamide

The title intermediate (154 mg, 0.23 mmol, 100%) was obtained as a whitesolid from Example 126 (149 mg, 0.23 mmol) analogously to Intermediate85.1. HPLC: ^(G)t_(Ret)=5.177 min; LC-MS: m/z 620.2 [M+H]⁺.

Example 130(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

A sealable reaction flask was charged with potassium phosphate (2.94 g,13.45 mmol), evacuated and heated for 1 h at 100° C. The reaction flaskwas back-filled with argon at RT and Intermediate 75.6 (2.35 g, 6.73mmol), Intermediate 130.1 (3.01 g, 6.73 mmol), dioxan (45 mL) and(+/−)-trans-1,2-diaminocyclohexane (0.167 mL, 1.345 mmol) were addedsubsequently. The reaction flask was carefully evacuated under vacuum(2×) and backfilled with argon (2×) and copper (I) iodide (0.256 g,1.345 mmol) were added. The reaction mixture was stirred 17 h at 95° C.The mixture was extracted between EtOAc (3×) and water (3×). The organicphases were washed with brine and dried over Na₂SO₄, filtered andevaporated to dryness. Purification of the residue by normal phasecolumn chromatography, eluting with DCM-MeOH-aq. 30% NH₄OH (200:10:1)followed by reverse phase prep-HPLC afforded the TFA salt which wasextracted between EtOAc (2×) and 1M aqueous NaHCO₃ (1×). The organicphases were washed with brine and dried over Na₂SO₄, filtered andevaporated to dryness. The residue was crystallized (EtOAc) to affordthe title compound as white crystals (1.84 g, 41%). HPLC:^(D)t_(Ret)=0.98 min; LC-MS: m/z 660.7 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆)0.95 (q, J=11.77 Hz, 2H), 1.11 (t, J=11.81 Hz, 2H), 1.17 (d, J=5.85 Hz,3H), 1.23 (d, J=5.85 Hz, 3H), 1.55-1.64 (m, 1H), 1.64-1.82 (m, 4H), 2.23(t, J=11.30 Hz, 1H), 2.67 (t, J=4.74 Hz, 2H), 2.78 (s, 3H), 2.95 (s,3H), 3.04 (s, 2H), 3.18 (t, J=4.84 Hz, 2H), 3.23-3.30 (m, 2H), 3.61 (d,J=19.98 Hz, 1H), 3.73 (s, 3H), 3.96 (d, J=19.98 Hz, 1H), 4.34-4.50 (m,1H), 5.96 (s, 1H), 6.52 (d, J=9.08 Hz, 1H), 6.84 (s, 1H), 6.95 (s, 1H),7.21 (d, J=8.88 Hz, 1H), 7.36 (s, 4H), 7.77 (s, 1H).

Intermediate 130.1:4-(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-1-methyl-piperazin-2-one

To a solution of Intermediate 130.2 (7.90 g, 13.06 mmol) in DCM (130 mL)was added TFA (30.2 mL, 392 mmol) at 0° C. The reaction mixture wasstirred at RT for 2.5 h. The solution was concentrated and the residueextracted between EtOAc (2×) and 1M aqueous NaHCO₃ (1×). The organicphases were washed with brine and dried over Na₂SO₄, filtered andevaporated to dryness. The residue was dissolved in MeOH (130 mL) at 0°C., triethylamin (27.3 mL, 196 mmol) was added and the mixture wasstirred for 30 min at RT. The reaction mixture was concentrated and theresidue extracted between EtOAc (2×) and 1M aqueous NaHCO₃ (1×). Theorganic phases were washed with brine and dried over Na₂SO₄, filteredand evaporated to dryness. Purification of the residue by normal phasecolumn chromatography, eluting with DCM-MeOH (20:1), crystallization(diisopropylether), gave the title compound as beige crystals (4.90 g,10.97 mmol, 84%). HPLC: ^(D)t_(Ret)=0.75 min; LC-MS: m/z 443.3 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆): 0.89-1.00 (m, 2H), 1.04-1.13 (m, 2H),1.55-1.68 (m, 3H), 1.71-1.80 (m, 2H), 2.16-2.26 (m, 1H), 2.61-2.68 (m,2H), 2.76 (s, 3H), 2.92 (s, 3H), 3.02 (s, 2H), 3.13-3.19 (m, 2H),3.27-3.31 (m, 2H), 6.47 (d, 1H), 7.65 (d, 1H), 8.15 (s, 1H).

Intermediate 130.2:[[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-(4-{[(5-iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-amino]-aceticacid methyl ester

To a solution of Intermediate 130.3 (5.80 g, 0.227 mmol), AcOH (1.57 mL,27.5 mmol) in DCM (250 mL) was added a solution ofmethyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (2.86 g, 16.5 mmol)in DCM (25 mL) at 0° C. The mixture was stirred for 20 min at 0° C.After addition of NaBH(OAc)₃ (5.83 g, 27.5 mmol), the cooling bath wasremoved and the suspension was stirred for 1 h at RT. To the reactionmixture was added carefully 1M aqueous NaHCO₃ (250 mL) followed byextraction with DCM (2×). The organic phases were dried over Na₂SO₄,filtered and evaporated. Purification of the residue by normal phasecolumn chromatography, eluting with DCM-MeOH (98:2), gave the titlecompound as beige oil (7.95 g, 13.15 mmol, 96%). HPLC: ^(D)t_(Ret)=1.14min; LC-MS: m/z 575.0 [M+H]⁺.

Intermediate 130.3:(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexylamino)-aceticacid methyl ester

To a solution of Intermediate 130.4 (6.28 g, 18 mmol) in DMF (180 mL)were successively added potassium carbonate (7.46 g, 54 mmol) and methyl2-bromoacetate (1.75 mL, 18.9 mmol) at −10° C. The suspension wasstirred for 17 h at −10° C. to RT. The reaction mixture was concentratedand the residue extracted between EtOAc (2×) and water (2×). The organicphases were washed with brine and dried over Na₂SO₄, filtered andevaporated to dryness. Purification of the residue by normal phasecolumn chromatography, eluting with DCM-MeOH-aq. 30% NH4OH (200:10:1),gave the title compound as beige oil (5.84 g, 13.86 mmol, 77%). HPLC:^(D)t_(Ret)=0.78 min; LC-MS: m/z 417.9 [M+H]⁺.

Intermediate 130.4:(Trans-4-amino-cyclohexylmethyl)-(5-iodo-pyridin-2-yl)-methyl-amine

To a solution of Intermediate 130.5 (26.5 g, 58.9 mmol) in DCM (295 mL)was added TFA (136 mL) at 0° C. The reaction mixture was stirred for 30min at 0° C. and an additional 1 h at RT. The solution was concentrated,extracted between 4M aqueous NaOH (300 mL) and DCM (4×). The organicphases were dried over Na₂SO₄, filtered and evaporated to dryness.Purification of the residue by normal phase column chromatography,eluting with DCM-MeOH-aq. 30% NH4OH (60:10:1), gave the title compoundas beige crystals (20.0 g, 57.4 mmol, 97%). HPLC: ^(D)t_(Ret)=0.68 min;LC-MS: m/z 346.3 [M+H]⁺.

Intermediate 130.5:(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

The mixture of Intermediate 130.6 (22.4 g, 92 mmol),2-fluoro-5-iodopyridine (21.4 g, 96 mmol), potassium carbonate (25.3 g,183 mmol) and DMSO (305 mL) was stirred for 21 h at 80° C. The reactionmixture was concentrated in vacuo and the residue extracted betweenEtOAc (2×) and 1M aqueous NaHCO₃ (1×). The organic phases were washedwith brine and dried over Na₂SO₄, filtered and evaporated to dryness.The residue was crystallized (TBME) to give the title compound as beigecrystals (26.7 g, 59.4 mmol, 65%). HPLC: ^(D)t_(Ret)=1.40 min; LC-MS:m/z 446.4 [M+H]⁺.

Intermediate 130.6: (Trans-4-methylaminomethyl-cyclohexyl)-carbamic acidtert-butyl ester

To a stirred solution of trans-(4-formyl-cyclohexyl)-carbamic acidtert-butyl (50 g, 218 mmol) and MeOH (2.2 L) was added HCl salt ofCH₃NH₂ (15.75 g) at RT. The mixture was stirred for 30 min at RT andthen cooled to 5° C. Addition of NaBH(OAc)₃ (72.9 g, 327 mmol) inportions during 45 min at 5° C. The reaction mixture was stirred for 1 hat 5° C. and then carefully quenched with 1M aqueous NaHCO₃ (300 mL) and2M NaOH. The resulting suspension was filtered over Hyflo, washed withMeOH and the filtrate was concentrated. The residue was extractedbetween EtOAc (2×) and 1M aqueous NaHCO₃ (1×). The organic phases werewashed with brine and dried over Na₂SO₄, filtered and evaporated todryness. Purification of the residue by normal phase columnchromatography, eluting with DCM-MeOH-aq. 30% NH₄OH (40:10:1), gave thetitle compound as white crystals (22.5 g, 92 mmol, 42%). TLC:R_(f)=0.33; LC-MS: m/z 243.1 [M+H]⁺.

Example 1312-{4-[({5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-2-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-isopropyl-acetamide

The mixture of Example 126 (253 mg, 0.398 mmol) and isopropylamine (3.41ml, 3.41 mmol) was heated for 1.5 h in methanol (3 mL) in the microwaveat 120° C. The mixture was concentrated to dryness and the residue waspurified by normal phase column chromatography (eluting withn-heptane-ethyl acetate), yielding the title compound as a beige solid(80 mg, 0.121 mmol, 99%). HPLC: ^(H)t_(Ret)=1.21 min; LC-MS: m/z 662.3[M+H]⁺.

Example 132(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (6.36 g, 9.74 mmol, 57%) was obtained as slightlyyellow crystals from Intermediate 75.6 (100 mg, 0.289 mmol) andIntermediate 132.1 (124 mg, 0.289), analogously to Example 130. HPLC:^(D)t_(Ret)=1.07 min; LC-MS: m/z 646.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆)0.87-1.09 (m, 4H), 1.15 (d, J=5.87 Hz, 3H), 1.20 (d, J=5.87 Hz, 3H),1.51-1.85 (m, 5H), 2.06-2.24 (m, 1H), 2.69 (s, 3H), 2.93 (s, 3H), 3.08(s, 2H), 3.27 (s, 2H), 3.56 (d, 1H), 3.71 (d, J=1.17 Hz, 3H), 3.93 (d,J=19.94 Hz, 1H), 4.01 (s, 2H), 4.27-4.47 (m, 1H), 5.93 (s, 1H), 6.50 (d,J=9.38 Hz, 1H), 6.81 (s, 1H), 6.92 (s, 1H), 7.13-7.24 (m, 1H), 7.33 (d,J=1.17 Hz, 4H), 7.74 (d, J=1.96 Hz, 1H).

Intermediate 132.1:1-(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-3-methyl-imidazolidin-4-one

To the solution of intermediate 132.2 (13.0 g, 29.7 mmol and EtOH (99mL) was added 37% aqueous solution of formaldehyde (22.09 ml, 297 mmol).The reaction mixture was stirred for 16 h at 80° C. The mixture wasconcentrated to dryness and the residue was purified by normal phasecolumn chromatography, eluting with DCM-MeOH-aq. 30% NH₄OH (200:20:1),gave the title compound after crystallization (diisopropyl ether-hexane)as white crystals (12.1 g, 28.0 mmol, 94%). HPLC: ^(D)t_(Ret)=0.94 min;LC-MS: m/z 429.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 0.82-1.06 (m, 4H),1.60 (m, 3H), 1.79 (m, 2H), 2.15 (m, 1H), 2.69 (s, 3H), 2.93 (s, 3H),3.08 (s, 2H), 3.27-3.31 (m, 2H), 4.01 (s, 2H), 6.49 (d, 1H), 7.65 (d,1H), 8.15 (s, 1H).

Intermediate 132.2:2-(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl-amino)-N-methyl-acetamide

The mixture of intermediate 130.3 (12.9 g, 30.6 mmol) and methylamine(33% in EtOH) (191 mL, 1.53 mol) was stirred 16 hours at 80° C. Themixture was concentrated to dryness and the residue was purified bynormal phase column chromatography, eluting with DCM-MeOH-aq. 30% NH₄OH(200:20:1), gave the title compound as a beige oil (13.0 g, 29.7 mmol,97%). HPLC: ^(D)t_(Ret)=0.68 min; LC-MS: m/z 417.3 [M+H]⁺.

Example 133(S)-1-(4-Chloro-phenyl)-7-isopropoxy-2-(6-{[4-(3-isopropyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-methyl-amino}-pyridin-3-yl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The mixture of Example 131 (80 mg, 0.121 mmol) and formaldehyde (0.090mL, 37% solution, 10 eq., 1.208 mmol) was heated for 5 h in 2-propanol(4 mL) at 85° C. The mixture was concentrated to dryness and the residuewas purified by reversed phase column chromatography. The fractionscontaining the product were pooled and worked up (addition of NaHCO₃),yielding the title compound as an off-white solid (46 mg, 0.068mmol, >98%). HPLC: ^(H)t_(Ret)=1.40 min; LC-MS: m/z 674.2 [M+H]⁺.

Intermediate 134.1:2-{4-[({5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-2-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-ethyl-acetamide

The title intermediate (120 mg, 0.178 mmol, 52%) was obtained as a whitesolid from Example 126 (217 mg, 0.34 mmol) and ethylamine analogously toIntermediate 85.1. HPLC: ^(G)t_(Ret)=5.521 min; LC-MS: m/z 648.3 [M+H]⁺.

Example 135(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(2-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

The mixture of Intermediate 135.1 (110 mg, 0.148 mmol) and 4 N HCl indioxane (0.738 mL, 2.95 mmol, 20 eq.) was stirred at room temperature indioxane (3 mL) for 3 h. The mixture was concentrated to dryness and theresidue was purified by reversed phase column chromatography (prepHPLC).The fractions containing the product were pooled and worked up (additionof NaHCO₃, removal of acetonitrile and extraction with DCM), yieldingthe title compound as a white solid (24.2 mg, 0.038 mmol, >99%). HPLC:^(H)t_(Ret)=1.54 min; LC-MS: m/z 646.3 [M+H]⁺.

Intermediate 135.1:4-{-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-3-oxo-piperazine-1-carboxylicacid tert-butyl ester

The title intermediate (110 mg, 0.148 mmol, 24.3%) was obtained as awhite solid from Intermediate 75.6 (210 mg, 0.607 mmol) and Intermediate135.2 (352 mg, 0.668 mmol) analogously to Example 75. HPLC:^(M)t_(Ret)=1.18 min; LC-MS: m/z 745.4 [M+H]⁺.

Intermediate 135.2:4-(4-{[(4-Iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl)-3-oxo-piperazine-1-carboxylicacid tert-butyl ester

To a solution of Intermediate 135.3 (0.51 g, 0.904 mmol) in DMF (15 mL)was added potassium tert-butoxide (0.230 g, 1.990 mmol) and the reactionwas heated at 80° C. for 5 h. The reaction was diluted with toluene andthe organic phase was washed with aq. NaHCO₃ solution and brine. Theorganic phase was dried over Na₂SO₄, filtered and concentrated in vacuoto obtain side products. The aqueous phase were pooled and extractedwith DCM to obtain the crude title product. The product was purified byautomated normal phase column chromatography (eluting withn-heptane—ethyl acetate), yielding the title compound as a brownish oil(350 mg, 0.66 mmol, 99%). HPLC: ^(M)t_(Ret)=1.40 min; LC-MS: m/z 528.1[M+H]⁺.

Intermediate 135.3:{2-[(2-Chloro-acetyl)-(4-{[(4-iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl)-amino]-ethyl}-carbamicacid tert-butyl ester

A solution of Intermediate 135.4 (0.50 g, 1.026 mmol) in DCM (20 mL) wasimmersed in an ice-bath. After 5 min, DIPEA (0.537 mL, 3.08 mmol) wasadded, then followed by chloracetyl chloride (0.099 mL, 1.231 mmol) wereadded slowly. The reaction was allowed to warm to RT and after 1 h, thestarting material was gone. The reaction mixture was diluted with ethylacetate and washed with aqueous NaHCO₃ solution and brine. The crudeproduct was purified by automated normal phase column chromatography(eluting with n-heptane—ethyl acetate), yielding the title compound as abrownish solid (0.51 g, 0.904 mmol). HPLC: ^(M)t_(Ret)=1.42 min; LC-MS:m/z 564.1 [M+H]⁺.

Intermediate 135.4:[2-(4-{[(4-Iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl-amino)-ethyl]-carbamicacid tert-butyl ester

The title intermediate 135.4 (0.50 g, 1.026 mmol) was obtained as acolorless oil from Intermediate 105.4 (1.54 g, 3.58 mmol) andN-Boc-2-aminoacetaldehyde (1.139 g, 7.16 mmol) analogously to Example52. HPLC: ^(M)t_(Ret)=0.98 min; LC-MS: m/z 488.2 [M+H]⁺.

Example 136(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(2-oxo-piperazin-1-yl)-cis-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

The mixture of intermediate 135.1 (110 mg, 0.148 mmol) and 4 N HCl indioxane (0.738 mL, 2.95 mmol, 20 eq.) was stirred at room temperature indioxane (3 ml) for 3 h. The mixture was concentrated to dryness and theresidue was purified by reversed phase column chromatography (prepHPLC).The fractions containing the product were pooled and worked up (additionof NaHCO₃, removal of acetonitrile and extraction with DCM), yieldingthe title compound as a white solid (12.3 mg, 0.019 mmol, >99%). HPLC:^(H)t_(Ret)=1.52 min; LC-MS: m/z 646.3 [M+H]⁺.

Example 137(S)-2-{5-[(Trans-4-amino-cyclohexylmethyl)-amino]-pyridin-2-yl}-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (111 mg, 0.203 mmol, quantitative) was obtained as abrown solid from Intermediate 137.1 (132 mg, 0.203 mmol) analogously toExample 77.3. HPLC: ^(F)t_(Ret)=1.937; LC-MS: m/z 549.4 [M+H]⁺.

Intermediate 137.1:[4-({6-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-ylamino}-methyl)-trans-cyclohexyl]-carbamicacid tert-butyl ester

The title intermediate (132 mg, 0.203 mmol, 28%) was obtained as a brownsolid from Intermediate 120.1 (367 mg, 0.850 mmol) and Intermediate 75.6(250 mg, 0.708 mmol) analogously to Example 75. HPLC: ^(F)t_(Ret)=1.455;LC-MS: m/z 649.3 [M+H]⁺.

Intermediate 138.1:1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 138.2 (150 g, 329 mmol) in DMF (650 mL)was successively added cesium carbonate (125 g, 658 mmol) and2-iodopropane (100 mL, 988 mmol), then the reaction mixture was heatedat 55° C. for 3 h. The reaction mixture was slowly poured into thestirred 2 L of iced water. Resulting mixture was extracted with 3 L ofEtOAc two times, then washed with 1 L of water 2 times and 0.5 L ofbrine.

Concentration in vacuo gave crude solid, which was stirred in 100 mL ofEtOAc at RT, then filtration and dry up gave the title intermediate(97.2 g, 281 mmol, 85%). HPLC: ^(E)t_(Ret)=4.99 min; LC-MS: m/z 346.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) 1.16 (dd, J=18.94, 6.05 Hz, 6H),3.28-3.54 (m, 2H), 3.70 (s, 3H), 4.32-4.47 (m, 1H), 5.53 (d, J=3.90 Hz,1H), 6.77 (s, 1H), 6.83 (s, 1H), 7.28 (d, 2H), 7.36 (d, 2H), 8.49 (d,J=3.90 Hz, 1H).

Intermediate 138.2:1-(4-Chloro-phenyl)-7-hydroxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a suspension of 4-hydroxy-3-methoxyphenylacetonitrile (150 g, 0.919mol) in phosphoric acid 85% (877 mL, 15.000 mol) was added4-chlorobenzaldehyde (168 g, 1.195 mol), then the reaction mixture washeated at 120° C. for 2 h. After cooling to 90° C., the reaction mixturewas slowly poured into the stirred 4 L of iced water. Resultingsuspension was stirred at RT for 2 h, then filtered and washed with 500mL of water 4 times. Crude and wet material was stirred in acetonitrile(1 L) at RT for 1 h, then filtration and dry up gave the titleintermediate (163.6 g, 0.539 mol, 58.6%). HPLC: ^(E)t_(Ret)=4.20 min;LC-MS: m/z 304.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) 3.25-3.53 (m, 2H),3.72 (s, 3H), 5.47 (d, J=3.12 Hz, 1H), 6.53 (s, 1H), 6.72 (s, 1H), 7.24(d, 2H), 7.37 (d, 2H), 8.42 (d, J=3.51 Hz, 1H), 8.86 (br. s., 1H).

Example 139{4-[({5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-aceticacid methyl ester

The title compound (300 mg, 0.467 mmol, 41%) was obtained as a yellowfoam from intermediate 139.1 (400 mg, 1.145 mmol) and intermediate 75.6(472 mg, 1.26 mmol) analogously to Example 75: HPLC: ^(D)t_(Ret)=1.40min; LC-MS: m/z 446.4 [M+H]⁺.

Intermediate 139.1:(4-{[(5-Bromo-pyrazin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl-amino)-aceticacid methyl ester

The title intermediate (570 mg, 1.52 mmol, 54%) was obtained as a beigecrystals from intermediate 139.2 (850 mg, 2.81 mmol) analogously tointermediate 130.3. HPLC: ^(D)t_(Ret)=0.68 min; LC-MS: m/z 371/373 [M]⁺.

Intermediate 139.2:(Trans-4-amino-cyclohexylmethyl)-(5-bromo-pyrazin-2-yl)-methyl-amine

The title intermediate (17.0 g, 55.7 mmol, 99%) was obtained as slightlyyellow crystals from intermediate 139.3 (22.5 g, 55.8 mmol) analogouslyto Intermediate 130.4. HPLC: ^(D)t_(Ret)=0.64 min; LC-MS: m/z 299/301[M]⁺.

Intermediate 139.3:(4-{[(5-Bromo-pyrazin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

To the stirred mixture of Intermediate 139.4 (16.6 g, 42.7 mmol),acetonitrile (2 L) and aqueous formaldehyde 37% (318 mL) was addedNaCNBH₄ (5.36 g, 85 mmol) at 10° C. Slowly addition of 4M HCl adjustedthe pH from 8.4 to 2.3. The reaction mixture was stirred for 4 h at10-16° C., while holding the pH at 2.3 (addition of 4M HCl). Addition ofa second portion of NaCNBH₄ (5.36 g, 85 mmol) and adjusting the pH from6.9 to 2.3 (addition of 4M HCl). The reaction mixture was stirred anadditional 1 h at 16° C., while holding the pH at 2.3 (addition of 4MHCl) and then concentrated. The residue was extracted between water andDCM (2×). The organic phases were washed with brine and dried overNa₂SO₄, filtered and evaporated to dryness. Purification of the residueby normal phase column chromatography, eluting with EtOAc-heptane (1:2),gave the title compound, after crystallization (TBME) as white crystals(13.53 g, 33.9 mmol, 79%). HPLC: ^(D)t_(Ret)=1.30 min; LC-MS: m/z399/401 [M]⁺.

Intermediate 139.4:{4-[(5-Bromo-pyrazin-2-ylamino)-methyl]-trans-cyclohexyl}-carbamic acidtert-butyl ester

To a stirred solution of trans-(4-formyl-cyclohexyl)-carbamic acidtert-butyl (30 g, 132 mmol), 2-amino-5-bromopyrazine (20.67 g, 119 mmol)and DCM (650 mL) was added NaBH(OAc)₃ (42.0 g, 198 mmol) and AcOH (22.67mL, 396 mmol) at 20° C. (slightly exothermic). The reaction mixture wasstirred for 18 h at RT. The reaction mixture was carefully quenched byslow addition of 1M aqueous NaHCO₃ (1 L). After 1 h stirring at RT, theorganic phase was separated and the aqueous phase was extracted withadditional DCM (600 mL). The combined organic phases were washed withbrine and dried over Na₂SO₄, filtered and evaporated to dryness.Purification of the residue by normal phase column chromatography,eluting with EtOAc-heptane (1:1), gave the title compound, aftercrystallization (TBME) as slightly yellow crystals (24.3 g, 62.4 mmol,47%). HPLC: ^(D)t_(Ret)=1.30 min; LC-MS: m/z 385/387 [M]⁺

Example 140(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-methoxy-2-(5-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Intermediate 140.1 (175 mg, 0.213 mmol) in dioxane(2.13 mL) was added 4M HCl (dioxane) (2.66 mL, 10.64 mmol) at 0° C. Thereaction mixture was stirred at RT for 1.5 h. The solution wasconcentrated and residue was dissolved in MeOH (2.13 mL) at 0° C.,triethylamine (0.445 mL, 3.19 mmol) was added and the mixture wasstirred for 1 h at RT. The reaction mixture was extracted between EtOAc(2×) and 1M aqueous NaHCO₃ (1×). The organic phases were washed withbrine and dried over Na₂SO₄, filtered and evaporated to dryness.Purification of the residue by normal phase column chromatography,eluting with DCM-MeOH (20:1), gave the title compound as slightly yellowfoam (118 mg, 0.177 mmol, 83%). HPLC: ^(D)t_(Ret)=0.97 min; LC-MS: m/z661.5 [M+H]⁺.

Intermediate 140.1:([2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-{4-[({5-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

The title intermediate (180 mg, 0.219 mmol, 91%) was obtained asslightly yellow foam from Example 139 (154 mg, 0.240 mmol) andmethyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (49.8 mg, 0.288mmol), analogously to Intermediate 130.2. HPLC: ^(D)t_(Ret)=1.36 min;LC-MS: m/z 793.6 [M+H]⁺.

Example 1412-{4-[({6-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-ethyl-acetamide

The title compound (73 mg, 0.113 mmol, 63%) was obtained as a yellowfoam from Example 120 (100 mg, 0.178 mmol) and 2-bromo-N-ethylacetamide(43 mg, 0.249 mmol) analogously to Intermediate 79.1. HPLC:^(F)t_(Ret)=1.016; LC-MS: m/z 648.5 [M+H]⁺.

Example 1422-{4-[({6-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-3-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-isopropyl-acetamide

The title compound (75 mg, 0.113 mmol, 64%) was obtained as a yellowfoam from Example 120 (100 mg, 0.178 mmol) and2-bromo-N-isopropylacetamide (42 mg, 0.231 mmol) analogously toIntermediate 79.1. HPLC: ^(F)t_(Ret)=1.035; LC-MS: m/z 662.5 [M+H]⁺

Example 143(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(2-oxo-azetidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Example 120 (125 mg, 0.222 mmol) in DCM (3 ml) weresuccessively added DMAP (1.356 mg, 0.0011 mmol), Et₃N (0.093 mL, 0.666mmol) and 3-chloro propionyl chloride (31 mg, 0.244 mmol) at 0° C. Theice bath was then removed and the yellow solution stirred for 1 h. Themixture was then poured onto DCM and washed with saturated NaHCO₃. Afterseparation, the organic phase was washed with H₂O and the aqueous phasere-extracted with DCM. The combined extracts were washed once withsaturated brine, dried over Na₂SO₄, filtered and concentrated todryness. The residue was then dissolved in DCM (5 mL) and NaH (60% inmineral oil, 13.62 mg, 0.341 mmol) was added. The reaction mixture wasthen stirred at RT for 15 h. The reaction mixture was then quenched withwater, poured into water and extracted with DCM. The organic phase waswashed with saturated brine, dried over Na₂SO₄, filtered andconcentrated to dryness. The crude residue was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,DCM/[DCM/EtOH 9: 1] 1:0→0:1) yielding the title compound as a yellowfoam (102 mg, 0.165 mmol, 97%). HPLC: ^(F)t_(Ret)=1.294; LC-MS: m/z617.4 [M+H]⁺.

Example 144(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridazin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (13 mg, 0.019 mmol, 11%) was obtained as slightlyyellow foam from Intermediate 75.6 (61 mg, 0.175 mmol) and Intermediate144.1 (77 mg, 0.192 mmol), analogously to Example 130. HPLC:^(D)t_(Ret)=0.93 min; LC-MS: m/z 661.5 [M+H]⁺.

Intermediate 144.1:4-(4-{[(6-Bromo-pyridazin-3-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-1-methyl-piperazin-2-one

To a solution of Intermediate 144.2 (335 mg, 0.628 mmol) in dioxane(6.28 mL) was added 4M HCl (dioxane) (7.84 mL, 31.4 mmol) at RT. Thereaction mixture was stirred at RT for 0.5 h. The solution wasconcentrated and the residue was dissolved in MeOH (6.28 mL) at 0° C.,triethylamine (1.31 mL, 9.41 mmol) was added and the mixture was stirredfor 50 min at RT. The reaction mixture was extracted between EtOAc (2×)and 1M aqueous NaHCO₃ (1×). The organic phases were washed with brineand dried over Na₂SO₄, filtered and evaporated to dryness. Purificationof the residue by normal phase column chromatography, eluting withDCM-MeOH (10:1), gave the title compound as beige crystals (230 mg,0.575 mmol, 92%). HPLC: ^(D)t_(Ret)=0.54 min; LC-MS: m/z 396/398 [M]⁺;¹H NMR (400 MHz, DMSO-d₆): 0.90-1.02 (m, 2H), 1.07-1.17 (m, 2H), 1.65(m, 3H), 1.78 (m, 2H), 2.23 (m, 1H), 2.66 (m, 2H), 2.77 (s, 3H), 3.03(m, 5H), 3.17 (m, 2H), 3.36 (m, 2H), 7.04 (d, 1H), 7.49 (d, 1H).

Intermediate 144.2:{(4-{[(6-Bromo-pyridazin-3-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-amino}-aceticacid methyl ester

The title intermediate (342 mg, 0.641 mmol, 96%) was obtained as a beigeoil from Intermediate 144.3 (250 mg, 0.667 mmol) analogously toIntermediate 130.2. HPLC: ^(D)t_(Ret)=0.96 min; LC-MS: m/z 528/530 [M]⁺.

Intermediate 144.3:(4-{[(6-Bromo-pyridazin-3-yl)-methyl-amino]-methyl}-trans-cyclohexyl-amino)-aceticacid methyl ester

The title intermediate (500 mg, 1.33 mmol, 50%) was obtained as beigecrystals from Intermediate 144.4 (800 mg, 2.65 mmol) analogously toIntermediate 130.3. HPLC: ^(D)t_(Ret)=0.57 min; LC-MS: m/z 371/373 [M]⁺.

Intermediate 144.4:(Trans-4-amino-cyclohexylmethyl)-(6-bromo-pyridazin-3-yl)-methyl-amine

The title intermediate (800 mg, 2.65 mmol, 96%) was obtained as a beigefoam from Intermediate 144.5 (1.15 g, 2.76 mmol) analogously toIntermediate 130.4. HPLC: ^(D)t_(Ret)=0.52 min; LC-MS: m/z 299/301 [M]⁺.

Intermediate 144.5:(4-{[(6-Bromo-pyridazin-3-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

The title intermediate (1.208 g, 2.90 mmol, 40%) was obtained asslightly yellow crystals from Intermediate 144.6 (2.80 g, 7.27 mmol)analogously to Intermediate 139.3. HPLC: ^(D)t_(Ret)=1.10 min; LC-MS:m/z 399/401 [M]⁺.

Intermediate 144.6:{4-[(6-Bromo-pyridazin-3-ylamino)-methyl]-trans-cyclohexyl}-carbamicacid tert-butyl ester

The title intermediate (2.0 g, 5.19 mmol, 32%) was obtained as whitecrystals from trans-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester(3.63 g, 15.97 mmol) and 6-bromo-pyridazin-3-ylamine (2.58 g, 14.37mmol), analogously to Intermediate 139.4. HPLC: ^(D)t_(Ret)=1.00 min;LC-MS: m/z 385/387 [M]⁺.

Example 1452-{4-[({5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-methyl-acetamide

The title compound (115 mg, 0.154 mmol, 85%) was obtained as slightlyorange foam from Example 139 (116 mg, 0.181 mmol), analogously toIntermediate 132.2. HPLC: ^(D)t_(Ret)=0.93 min; LC-MS: m/z 635.5 [M+H]⁺.

Example 146(S)-1-(4-Chloro-phenyl)-2-(5-{[4-(3-ethyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-methyl-amino}-pyridin-2-yl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The mixture of Example 141 (63 mg, 0.097 mmol) and formaldehyde (0.074mL, 37% solution, 10 eq., 0.612 mmol) in EtOH (3 mL) was heated for 48 hat 60° C. The mixture was concentrated to dryness and the residue waspurified by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, DCM/[DCM/MeOH 9: 1] 1:0→1:1) yielding the titlecompound as a yellow solid (64 mg, 0.097 mmol, 100%), HPLC:^(F)t_(Ret)=1.132; LC-MS: m/z 660.3 [M+H]⁺.

Example 147(S)-1-(4-Chloro-phenyl)-2-{6-[(3-hydroxy-cyclobutylmethyl)-methyl-amino]-pyridin-3-yl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (4 mg, 0.007 mmol, 7%) was obtained as a yellow solidfrom Intermediate 147.2 (65 mg, 0.104 mmol) and Intermediate 75.6 (36mg, 0.104 mmol) analogously to Example 75. HPLC: ^(F)t_(Ret)=0.989;LC-MS: m/z 536.4 [M+H]⁺.

Intermediate 147.2: 4-Nitro-benzoic acid3-{[(5-iodo-pyridin-2-yl)-methyl-amino]-methyl}-cyclobutyl ester

To a solution of Intermediate 147.3 (311 mg, 0.590 mmol) in3-ethyl-pentan-3-ol (3 mL) was added to 2-bromo-5-iodopyridine (184 mg,0.649 mmol) and Et₃N (0.247 mL, 1.769 mmol). The yellow suspension wasirradiated in a microwave to 150° C. for 8 h. After cooling, the mixturewas poured onto EtOAc and water. After phase separation, the aqueousphase was re-extracted twice with EtOH. The combined organic extractswere washed with H₂O, saturated brine, dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, DCM/[DCM/EtOH 9:1] 1:0→0:1)) to yield the title compound (66mg, 0.104 mmol, 17%), HPLC: ^(F)t_(Ret)=1.454; LC-MS: m/z 468.2 [M+H]⁺.

Intermediate 147.3: 4-Nitro-benzoic acid 3-methylaminomethyl-cyclobutylester

To a solution of Intermediate 147.4 (1.811 g, 6.32 mmol) in a mixture ofDCM (50 mL) and MeOH (5 mL) was added Et₃N (1.321 mL, 9.48 mmol) at RT.To the resulting suspension were successively added at RT AcOH (1.266mL, 22.11 mmol), formaldehyde (37% in water, 0.941 mL, 12.64 mmol) andNaBH(OAc)₃ (2.82 g, 12.64 mmol). The reaction mixture was stirred at RTfor 1 h then diluted with DCM and washed with a 2M aqueous Na₂CO₃solution (2×). The organic phase was dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, DCM/[DCM/EtOH/NH3 aq. 90:9: 1] 1:0→0:1)) to yield the titlecompound (311 mg, 0.590 mmol, 9%) as a light yellow oil, HPLC:^(F)t_(Ret)=0.683; LC-MS: m/z 265.2 [M+H]⁺.

Intermediate 147.4: 4-Nitro-benzoic acid 3-aminomethyl-cyclobutyl esterHCl salt

To a solution of Intermediate 147.5 (5.15 g, 11.76 mmol) in Et₂O (150mL) was added a solution of HCl (1M in Et₂O, 47 mL, 47 mmol). Thereaction mixture was stirred at RT for 24 h. The precipitate wascollected by filtration and the cake washed with Et₂O, dried undervacuum, yielding the title intermediate as a colorless solid (2.906 g,10.14 mmol, 86%), HPLC: ^(F)t_(Ret)=0.885; LC-MS: m/z 251.2 [M]⁺.

Intermediate 147.5: 4-Nitro-benzoic acid3-(tert-butoxycarbonylamino-methyl)-cyclobutyl ester

To an ice-cooled solution of (3-Hydroxy-cyclobutylmethyl)-carbamic acidtert-butyl ester (6.98 g, 34.7 mmol), 4-nitrobenzoic acid (11.59 g, 69.4mmol) and triphenylphosphine (18.19 g, 69.4 mmol) in THF (1 L) was addeda solution of DIAD (14.76 g, 69.4 mmol) in THF (10 mL). After removal ofthe ice bath, the mixture was stirred at RT for 15 h. The mixture wasconcentrated to dryness and the oily residue was purified normal phasecolumn chromatography (elution with DCM) yielding the title intermediateas a yellow solid (9.89 g, 22.58 mmol, 65%), HPLC: ^(F)t_(Ret)=1.354;LC-MS: m/z 368.3 [M+NH4]⁺.

Example 148(S)-1-(4-Chloro-phenyl)-7-isopropoxy-2-(5-{[4-(3-isopropyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-methyl-amino}-pyridin-2-yl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (68 mg, 0.101 mmol, 89%) was obtained as a yellowfoam from Example 142 (75 mg, 0.113 mmol) analogously to Example 146.HPLC: ^(F)t_(Ret)=1.165; LC-MS: m/z 674.3 [M+H]⁺.

Example 149(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (1.23 g, 1.88 mmol, 33%) was obtained as slightlywhit crystals from Intermediate 75.6 (2.00 g, 5.73 mmol) andIntermediate 149.1 (2.21 g, 5.73 mmol), analogously to Example 130.HPLC: ^(D)t_(Ret)=1.15 min; LC-MS: m/z 647.6 [M+H]⁺; ¹H NMR (600 MHz,DMSO-d₆) 0.93-1.12 (m, 4H), 1.23 (dd, J=16.35, 6.05 Hz, 6H), 1.64 (d,J=10.90 Hz, 3H), 1.81 (d, J=10.90 Hz, 2H), 2.18 (t, J=10.29 Hz, 1H),2.71 (s, 3H), 3.02 (s, 3H), 3.11 (s, 2H), 3.35-3.42 (m, 2H), 3.60 (d,J=19.38 Hz, 1H), 3.73 (s, 3H), 3.81 (d, J=19.38 Hz, 1H), 4.04 (s, 2H),4.52 (quin, J=6.05 Hz, 1H), 6.40 (s, 1H), 6.87 (s, 1H), 7.20 (s, 1H),7.34 (s, 4H), 7.91 (s, 1H), 8.17 (s, 1H).

Intermediate 149.1:1-(4-{[(5-Bromo-pyrazin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-3-methyl-imidazolidin-4-one

The title intermediate (10.4 g, 26.9 mmol, 96%) was obtained as beigecrystals from Intermediate 149.2 (10.5 g, 28.1 mmol), analogously toIntermediate 132.1. HPLC: ^(D)t_(Ret)=0.85 min; LC-MS: m/z 382/384 [M]⁺.

Intermediate 149.2:2-(4-{[(5-Bromo-pyrazin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl-amino)-N-methyl-acetamide

The title intermediate (10.7 g, 28.6 mmol, 93%) was obtained as whitecrystals from Intermediate 139.1 (12.0 g, 30.7 mmol), analogously toIntermediate 132.2. HPLC: ^(D)t_(Ret)=0.71 min; LC-MS: m/z 370/372 [M]⁺.

Example 150{4-[({2-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrimidin-5-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-aceticacid methyl ester

The title compound (68 mg, 0.104 mmol, 30%) was obtained as a slightlyyellow foam from Intermediate 75.6 (120 mg, 0.344 mmol) and Intermediate150.1 (142 mg, 0.378 mmol), analogously to Example 130. HPLC:^(D)t_(Ret)=0.93 min; LC-MS: m/z 636.4 [M+H]⁺.

Intermediate 150.1:(4-{[(2-Bromo-pyrimidin-5-yl)-methyl-amino]-methyl}-trans-cyclohexyl-amino)-aceticacid methyl ester

The title intermediate (540 mg, 1.44 mmol, 54%) was obtained as whitecrystals from Intermediate 150.2 (830 mg, 2.64 mmol) analogously toIntermediate 130.3. HPLC: ^(D)t_(Ret)=0.55 min; LC-MS: m/z 371/373 [M]⁺.

Intermediate 150.2:(Trans-4-amino-cyclohexylmethyl)-(2-bromo-pyrimidin-5-yl)-methyl-amine

The title intermediate (830 mg, 2.64 mmol, 97%) was obtained as whitefoam from Intermediate 150.3 (1.10 g, 2.73 mmol) analogously toIntermediate 130.4. HPLC: ^(D)t_(Ret)=0.54 min; LC-MS: m/z 299/301 [M]⁺.

Intermediate 150.3:(4-{[(2-Bromo-pyrimidin-5-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

The title intermediate (820 mg, 2.03 mmol, 81%) was obtained as slightlyyellow crystals from Intermediate 150.4 (1.0 g, 2.52 mmol) analogouslyto Intermediate 139.3. HPLC: ^(D)t_(Ret)=1.14 min; LC-MS: m/z 399/401[M]⁺.

Intermediate 150.4:{4-[(2-Bromo-pyrimidin-5-ylamino)-methyl]-trans-cyclohexyl}-carbamicacid tert-butyl ester

The title intermediate (2.71 g, 6.82 mmol, 49%) was obtained as whitecrystals from trans-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester(3.19 g, 14.03 mmol) and 2-bromo-pyrimidin-5-ylamine (2.20 g, 12.63mmol), analogously to Intermediate 139.4. HPLC: ^(D)t_(Ret)=1.08 min;LC-MS: m/z 385/387 [M]⁺.

Example 1511-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(2,2,2-trifluoro-ethoxy)-1,4-dihydro-2H-isoquinolin-3-one

To the solution of Intermediate 26.3 (100 mg, 0.236 mmol) and DMF (2.0mL) was added toluene-4-sulfonic acid 2,2,2-trifluoro-ethyl ester (72.1mg, 0.284 mmol) and potassium carbonate (65.4 mg, 0.473 mmol). Themixture was stirred for 15 min at 140° C. The reaction mixture wasextracted between DCM (2×) and 1M aqueous NaHCO₃ (1×). The organicphases were dried over Na₂SO₄, filtered and evaporated to dryness.Purification of the residue by normal phase column chromatography,eluting with EtOAc-heptane, gave the title compound as a beige foam (42mg, 0.083 mmol, 35%). HPLC: ^(J)t_(Ret)=6.02 min; LC-MS: m/z 505.4[M+H]⁺.

Example 152(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(4-methyl-3-oxo-ipiperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrimidin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (7.0 mg, 0.010 mmol, 4.5%) was obtained as a slightlyorange foam from Intermediate 75.6 (80 mg, 0.229 mmol) and Intermediate152.1 (90 mg, 0.252 mmol), analogously to Example 130. HPLC:^(D)t_(Ret)=0.91 min; LC-MS: m/z 661.5 [M+H]⁺.

Intermediate 152.1:4-(4-{[(2-Chloro-pyrimidin-5-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-1-methyl-piperazin-2-one

The title intermediate (99 mg, 0.278 mmol, 85%) was obtained as slightlyyellow crystals from Intermediate 152.2 (175 mg, 0.328 mmol) analogouslyto Intermediate 144.1. HPLC: ^(D)t_(Ret)=0.54 min; LC-MS: m/z 352.3[M+H]⁺.

Intermediate 152.2:{(4-{[(2-Bromo-pyrimidin-5-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-amino}-aceticacid methyl ester

The title intermediate (180 mg, 0.337 mmol, 84%) was obtained as a beigeoil from Intermediate 150.1 (150 mg, 0.40 mmol) analogously toIntermediate 130.2. HPLC: ^(D)t_(Ret)=1.01 min; LC-MS: m/z 528/530 [M]⁺.

Example 153(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridazin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (2.0 mg, 0.010 mmol, 1.7%) was obtained as a slightlyyellow foam from Intermediate 75.6 (60 mg, 0.172 mmol) and Intermediate153.1 (77 mg, 0.189 mmol), analogously to Example 130. HPLC:^(D)t_(Ret)=1.06 min; LC-MS: m/z 647.2 [M+H]⁺.

Intermediate 153.1:1-(4-{[(6-Bromo-pyridazin-3-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-3-methyl-imidazolidin-4-one

The title intermediate (192 mg, 0.497 mmol, 94%) was obtained as whitecrystals from Intermediate 153.2 (195 mg, 0.527 mmol) analogously toIntermediate 132.1. HPLC: ^(D)t_(Ret)=0.65 min; LC-MS: m/z 382/384 [M]⁺.

Intermediate 153.2:2-(4-{[(6-Bromo-pyridazin-3-yl)-methyl-amino]-methyl}-trans-cyclohexyl-amino)-N-methyl-acetamide

The title intermediate (200 mg, 0.513 mmol, 96%) was obtained as a beigefoam from Intermediate 144.3 (200 mg, 0.533 mmol) analogously toIntermediate 132.2. HPLC: ^(D)t_(Ret)=0.49 min; LC-MS: m/z 370/372 [M]⁺.

Example 1541-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(2-methyoxyethoxy)-1,4-dihydro-2H-isoquinolin-3-one

To the solution of Intermediate 26.3 (60 mg, 0.137 mmol) and DMF (0.27mL) was added 2-bromoethyl methyl ether (20.9 mg, 0.150 mmol) andpotassium carbonate (28.4 mg, 0.205 mmol). The mixture was stirred for90 min at 100° C. The reaction mixture was extracted between EtOAc (2×)and water-brine 9:1 (1×). The organic phases were washed with brine anddried over Na₂SO₄, filtered and evaporated to dryness. Purification ofthe residue by normal phase column chromatography, eluting withEtOAc-heptane (1:4), gave the title compound as a beige foam (20 mg,0.041 mmol, 30%). HPLC: ^(D)t_(Ret)=1.13 min; LC-MS: m/z 481.4 [M+H]⁺.

Example 1551-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-[(S)-1-(tetrahydro-furan-2-yl)-methoxy]-1,4-dihydro-2H-isoquinolin-3-one

The title compound (23 mg, 0.045 mmol, 39%) was obtained as a beige foamfrom Intermediate 26.3 (50 mg, 0.114 mmol) and (S)-tetrahydrofurfurylalcohol (17.8 mg, 0.171 mmol), analogously to Example 156. HPLC:^(D)t_(Ret)=1.18 min; LC-MS: m/z 507.1 [M+H]⁺.

Example 1561-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-[(R)-1-(tetrahydro-furan-2-yl)methoxy-1,4-dihydro-2H-isoquinolin-3-one

To the solution of Intermediate 26.3 (50 mg, 0.114 mmol) in THF (0.57mL) was added subsequently (R)-tetrahydrofurfuryl alcohol (17.8 mg,0.171 mmol), triphenylphosphine (48.8 mg, 0.182 mmol) anddi-isopropylazodicarboxylate (34.3 mg, 0.160 mmol) at 0° C. The mixturewas stirred for 22 h at RT. The reaction mixture was extracted betweenEtOAc (2×) and 1M aqueous NaHCO₃ (1×). The organic phases were washedwith brine and dried over Na₂SO₄, filtered and evaporated to dryness.Purification of the residue by normal phase column chromatography,eluting with DCM-EtOAc (2:1→1:1), gave the title compound as a beigefoam (21 mg, 0.041 mmol, 36%). HPLC: ^(D)t_(Ret)=1.18 min; LC-MS: m/z507.3 [M+H]⁺.

Example 1571-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-((R)-2-methoxy-propoxy)-1,4-dihydro-2H-isoquinolin-3-one

To the solution of Intermediate 26.3 (40 mg, 0.095 mmol) in DCM (2.0 mL)was added subsequently (S)-(+)-2-methoxypropanol (12.8 mg, 0.142 mmol),di-tert-butylazo-dicarboxylate (32.7 mg, 0.142 mmol) andtriphenylphosphine (34.7 mg, 0.132 mmol) at 0° C. The mixture wasstirred for 18 h at RT. The reaction mixture then directly subjected topurification by reverse phase prep-HPLC (Waters system gave the titlecompound as a beige foam (10 mg, 0.020 mmol, 21%). HPLC:^(J)t_(Ret)=5.340; LC-MS: m/z 495.3 [M+H]⁺.

Example 1581-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(-2-methoxy-1-methyl-ethoxy))-1,4-dihydro-2H-isoquinolin-3-one

The title compound (38 mg, 0.077 mmol, 65%) was obtained as a beige foamfrom Intermediate 26.3 (50 mg, 0.118 mmol) and 1-methoxy-2-propanol,analogously to Example 157. HPLC: ^(J)t_(Ret)=5.11; LC-MS: m/z 495.2[M+H]⁺.

Example 1631-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (25 mg, 0.039 mmol, 42%) was obtained as a whitesolid from Intermediate 163.1 (74 mg, 0.093 mmol) analogously to Example79. HPLC: ^(C)t_(Ret)=8.718 min; LC-MS: m/z 645.2 [M+H]⁺.

Intermediate 163.1:((2-tert-Butoxycarbonylamino-ethyl)-{-[({4-[1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

The title intermediate (110 mg, 0.148 mmol, 24.3%) was obtained as anoff-white solid from Intermediate 138.1 (200 mg, 0.578 mmol) andIntermediate 106.2 (388 mg, 0.694 mmol) analogously to Example 75. HPLC:^(M)t_(Rert)=2.00 min; LC-MS: m/z 777.2 [M+H]⁺.

Example 164(S)-2-[4-(3-Amino-1H-pyrazol-4-yl)-phenyl]-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

A mixture of Intermediate 164.1 (193 mg, 0.318 mmol), hydrazine hydrate(0.08 mL, 1.59 mmol) and acetic acid (0.09 mL, 1.59 mmol) in toluene(1.0 mL) was heated at reflux for 16 h. The reaction mixture was pouredinto the stirred iced water. The aqueous layer was extracted twice withEtOAc, the combined organic layers were washed with water and brine,dried (Na₂SO₄), filtered and concentrated. The residue was purified bycolumn chromatography to afford the title compound (23 mg, 0.044 mmol,14%) as a white solid. HPLC: ^(G)t_(Ret)=6.802 min; LC-MS: m/z 503.4[M+H]⁺.

Intermediate 164.1:(Z)-2-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-3-dimethylamino-acrylonitrile

A mixture of Intermediate 164.2 (150 mg, 0.32 mmol) anddimethylformamide dimethylacetal (0.09 mL, 0.65 mmol) in toluene (0.5mL) was heated at reflux for 4 h. The reaction mixture was concentratedin vacuo, which gave the title intermediate (198 mg, 0.32 mmol, 100%).It was used for the next step without further purification. HPLC:^(G)t_(Ret)=7.413 min; LC-MS: m/z 516.4 [M+H]⁺.

Intermediate 164.2:{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-acetonitrile

The title intermediate (147 mg, 0.32 mmol, 44.1%) was obtained as awhite solid from Intermediate 75.6 (250 mg, 0.72 mmol) and(4-Iodo-phenyl)-acetonitrile (193 mg, 0.79 mmol) analogously to Example75. HPLC: ^(G)t_(Ret)=9.082 min; LC-MS: m/z 461.1 [M+H]⁺.

Intermediate 165.1:(Z)-2-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-3-dimethylamino-but-2-enenitrile

A mixture of Intermediate 164.2 (150 mg, 0.32 mmol) andN,N-dimethylacetamide dimethylacetal (0.10 mL, 0.65 mmol) in toluene(0.5 mL) was stirred for 4 h under reflux. The reaction mixture wasconcentrated in vacuo, which gave the title intermediate (187 mg, 0.32mmol, 98%). It was used for the next step without further purification.HPLC: ^(G)t_(Ret)=7.614 min; LC-MS: m/z 530.5 [M+H]⁺.

Intermediate 166.1:4-{4-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-3,5-dimethyl-pyrazole-1-carboxylicacid tert-butyl ester

The title intermediate (297 mg, 0.48 mmol, 38%) was obtained as a orangesolid from Intermediate 166.2 (700 mg, 1.27 mmol) and3,5-Dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (453 mg, 1.40 mmol) analogously to Example 36. ¹HNMR (400 MHz, DMSO-d₆) 1.21 (dd, 6H), 1.55 (s, 9H), 2.11 (s, 3H), 2.36(s, 3H), 3.62 (d, J=19.92 Hz, 1H), 3.71 (s, 3H), 3.84 (d, J=19.92 Hz,1H), 4.40-4.49 (m, 1H), 6.16 (s, 1H), 6.85 (s, 1H), 7.14 (s, 1H), 7.26(dd, 4H), 7.38 (s, 4H).

Intermediate 166.2:1-(4-Chloro-phenyl)-2-(4-iodo-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (1.97 g, 3.52 mmol, 56%) was obtained as a whitesolid from Intermediate 34.1 (2.15 g, 6.29 mmol) and Intermediate 96.1(1.53 g, 6.29 mmol) analogously to Example 1. HPLC: ^(E)t_(Ret)=5.925min; LC-MS: m/z 548.2 [M+H]⁺.

Example 1671-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-7-(1-hydroxy-cyclopropylmethoxy))-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (31 mg, 0.063 mmol, 66%) was obtained as a beige foamfrom Intermediate 26.3 (40 mg, 0.095 mmol) and[1-(tetrahydro-pyran-2-yloxy)-cyclopropyl]-methanol (24.4 mg, 0.142mmol), analogously to Example 157. HPLC: ^(J)t_(Ret)=4.795; LC-MS: m/z493.4 [M+H]⁺.

Example 1681-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(3-methoxy-propoxy)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (15 mg, 0.031 mmol, 32%) was obtained as a beige foamfrom Intermediate 26.3 (40 mg, 0.095 mmol) and 1-bromo-3-methoxypropane(15.9 mg, 0.104 mmol), analogously to Example 154. HPLC:^(J)t_(Ret)=5.417; LC-MS: m/z 495.4 [M+H]⁺.

Example 169(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[1-(2-oxo-piperazin-1-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one

The title compound (10 mg, 0.018 mmol, 34%) was obtained as a colorlesssolid from Intermediate 169.1 (50 mg, 0.0.054 mmol) analogously toExample 77.3. HPLC: ^(F)t_(Ret)=0.928; LC-MS: m/z 550.0 [M+H]⁺.

Intermediate 169.1:4-(1-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-3-oxo-piperazine-1-carboxylicacid tert-butyl ester

The title intermediate (50 mg, 0.054 mmol, 31%) was obtained as a brownsolid from Intermediate 169.2 (90 mg, 0.209 mmol) and Intermediate 75.6(60 mg, 0.174 mmol) analogously to Example 75. HPLC: ^(F)t_(Ret)=1.352.

Intermediate 169.2:4-[1-(4-Iodo-phenyl)-ethyl]-3-oxo-piperazine-1-carboxylic acidtert-butyl ester

To a solution of Boc-3-oxopiperazine (67 mg, 0.328 mmol) in DMF (3 mL)was added NaH (60% in mineral oil, 13 mg, 0.328 mmol). After cooling to0° C., 1-(1-Bromo-ethyl)-4-iodo-benzene (100 mg, 0.273 mmol) was added.The ice bath was removed and the mixture stirred at RT for 2 h and thenpartitioned between EtOAc and a solution of NH₄Cl. After separation, theaqueous phase was re-extracted twice with DCM and the combined organicextracts were washed with H₂O, saturated brine, dried over Na₂SO₄,filtered and evaporated to dryness. The resulting crude material waspurified by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, DCM/EtOac] 1:0→0:1)) to yield the titleintermediate (90 mg, 0.188 mmol, 68%) as a colorless solid. HPLC:^(F)t_(Ret)=1.276.

Example 1701-(4-Chloro-phenyl)-2-(4-dimethylamino-phenyl)-6-methoxy-7-(oxetan-2-ylmethoxy)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (10 mg, 0.02 mmol, 28%) was obtained as a beige foamfrom Intermediate 26.3 (30 mg, 0.071 mmol) and oxetan-2-yl-methanol (7.5mg, 0.085 mmol), analogously to Example 157. HPLC: ^(J)t_(Ret)=4.968;LC-MS: m/z 493.4 [M+H]⁺.

Example 1711-(4-Chloro-phenyl)-7-(2,2-difluoro-ethoxy)-2-(4-dimethylamino-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To the solution of Intermediate 26.3 (30 mg, 0.071 mmol) and DMF (1.0mL) was added 1,1-difluoro-2-iodo-ethane (20.4 mg, 0.106 mmol) andpotassium carbonate (29.4 mg, 0.213 mmol). The mixture was stirred for18 h at 50° C. The reaction mixture was extracted between EtOAc (2×) andwater—brine 9:1 (1×). The organic phases were washed with brine anddried over Na₂SO₄, filtered and evaporated to dryness. The residue wassubjected to purification by reverse phase prep-HPLC (Waters system gavethe title compound as a beige foam (12 mg, 0.024 mmol, 34%). HPLC:^(J)t_(Ret)=5.59; LC-MS: m/z 487.4 [M+H]⁺.

Example 172{4-[({5-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-aceticacid methyl ester

The title compound (73 mg, 0.101 mmol, 31%) was obtained as a orangefoam from Intermediate 138.1 (115 mg, 0.329 mmol) and Intermediate 139.1(142 mg, 0.362 mmol), analogously to Example 130. HPLC: ^(D)t_(Ret)=1.00min; LC-MS: m/z 636.5 [M+H]⁺.

Example 1732-{4-[({5-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyrazin-2-yl}-methyl-amino)-methyl]-trans-cyclohexylamino}-N-methyl-acetamide

The title compound (37 mg, 0.058 mmol, 59%) was obtained as a yellowfoam from Example 172 (70 mg, 0.097 mmol), analogously to Example 132.2.HPLC: ^(D)t_(Ret)=0.97 min; LC-MS: m/z 635.6 [M+H]⁺.

Example 1741-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (29 mg, 0.044 mmol, 79%) was obtained as a yellowfoam from Example 173 (36 mg, 0.056 mmol), analogously to Example 132.1.HPLC: ^(D)t_(Ret)=0.97 min; LC-MS: m/z 635.6 [M+H]⁺.

Example 1751-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (29 mg, 0.044 mmol, 79%) was obtained as a yellowfoam from Intermediate 138.1 (35 mg, 0.100 mmol) and Intermediate 130.1(50 mg, 0.100 mmol), analogously to Example 130. HPLC: ^(D)t_(Ret)=0.97min; LC-MS: m/z 660.7 [M+H]⁺.

Intermediate 176.1:([2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-{4-[({4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-2-fluoro-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

The title intermediate (48 mg, 0.059 mmol, 63%) was obtained as a whitesolid from Intermediate 176.2 (68 mg, 0.094 mmol) andMethyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (21.1 mg, 0.12 mmol)analogously to Intermediate 79.2. HPLC: ^(G)t_(Ret)=7.877 min; LC-MS:m/z 809.8 [M+H]⁺.

Intermediate 176.2:{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-2-fluoro-phenyl}-methyl-amino)-methyl]-trans-cyclohexylamino}-aceticacid methyl ester

The title intermediate (361 mg, 0.52 mmol, 38.3%) was obtained as awhite solid from Intermediate 75.6 (470 mg, 1.36 mmol) and Intermediate176.3 (721 mg, 1.49 mmol) analogously to Example 75. HPLC:^(G)t_(Ret)=6.786 min; LC-MS: m/z 652.5 [M+H]⁺.

Intermediate 176.3:(4-{[(2-Fluoro-4-iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl-amino)-aceticacid methyl ester

The title intermediate (3.06 g, 6.34 mmol, 70.9%) was obtained as awhite solid from Intermediate 176.4 (3.6 g, 8.94 mmol) andmethyl-2-bromoacetate (0.95 mL, 10.3 mmol) analogously to Intermediate79.1. HPLC: ^(G)t_(Ret)=6.556 min; LC-MS: m/z 435.3 [M+H]⁺.

Intermediate 176.4:(Trans-4-amino-cyclohexylmethyl)-(2-fluoro-4-iodo-phenyl)-methyl-amine

The title intermediate (3.62 g, 8.99 mmol, 94%) was obtained as a whitesolid from Intermediate 176.5 (4.9 g, 9.54 mmol) analogously toIntermediate 77.3. HPLC: ^(G)t_(Ret)=5.992 min; LC-MS: m/z 362.8 [M+H]⁺.

Intermediate 176.5:(4-{[(2-Fluoro-4-iodo-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

The title intermediate (4.9 g, 9.54 mmol, 91%) was obtained as a whitesolid from Intermediate 176.6 (4.7 g, 10.4 mmol) and 37% water solutionof formaldehyde (1.56 mL, 20.9 mmol) analogously to Intermediate 77.1.HPLC: ^(G)t_(Ret)=8.720 min; LC-MS: m/z 463.3 [M+H]⁺.

Intermediate 176.6:{4-[(2-Fluoro-4-iodo-phenylamino)-methyl]-trans-cyclohexyl}-carbamicacid tert-butyl ester

The title intermediate (4.8 g, 10.7 mmol, 97%) was obtained as a whitesolid from trans-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester(3.0 g, 13.2 mmol) and 2-fluoro-4-iodoaniline (2.66 g, 11 mmol)analogously to Intermediate 75.7. HPLC: ^(G)t_(Ret)=8.586 min; LC-MS:m/z 393.2 [M-BOC+HCOOH]⁺.

Intermediate 177.1:([2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-{-4-[({4-[(S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-fluoro-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl}-amino)-aceticacid methyl ester

The title intermediate (48 mg, 0.059 mmol, 63.2%) was obtained as awhite solid from Intermediate 177.2 (68 mg, 0.094 mmol) andMethyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (21.1 mg, 0.12 mmol)analogously to Intermediate 79.2. HPLC: ^(G)t_(Ret)=7.854 min; LC-MS:m/z 809.8 [M+H]⁺.

Intermediate 177.2:{4-[({4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-fluoro-phenyl}-methyl-amino)-methyl]-trans-cyclohexyl-amino}-aceticacid methyl ester

The title intermediate (70 mg, 0.097 mmol, 11.3%) was obtained as awhite solid from Intermediate 75.6 (295 mg, 0.85 mmol) and Intermediate177.3 (364 mg, 0.94 mmol) analogously to Example 75. HPLC:^(G)t_(Ret)=6.997 min; LC-MS: m/z 652.7 [M+H]⁺.

Intermediate 177.3:(4-{[(4-Bromo-3-fluoro-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl-amino)-aceticacid methyl ester

The title intermediate (360 mg, 0.93 mmol, 21.6%) was obtained as awhite solid from Intermediate 177.4 (1.36 g, 4.31 mmol) andmethyl-2-bromoacetate (0.42 mL, 4.53 mmol) analogously to Intermediate79.1. HPLC: ^(G)t_(Ret)=6.333 min; LC-MS: m/z 387.3 [M+H]⁺.

Intermediate 177.4:(Trans-4-amino-cyclohexylmethyl)-(4-bromo-3-fluoro-phenyl)-methyl-amine

The title intermediate (1.36 g, 4.31 mmol, 74.7%) was obtained as awhite solid from Intermediate 177.5 (2.4 g, 5.78 mmol) analogously toIntermediate 77.3. HPLC: ^(G)t_(Ret)=6.245 min; LC-MS: m/z 317.2 [M+H]⁺.

Intermediate 177.5:(4-{[(4-Bromo-3-fluoro-phenyl)-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

The title intermediate (2.42 g, 5.83 mmol, 75%) was obtained as a whitesolid from Intermediate 177.6 (3.1 g, 7.72 mmol) and 37% water solutionof formaldehyde (1.15 mL, 15.4 mmol) analogously to Intermediate 77.1.HPLC: ^(G)t_(Ret)=8.689 min; LC-MS: m/z 417.3 [M+H]⁺.

Intermediate 177.6:{4-[(4-Bromo-3-fluoro-phenylamino)-methyl]-trans-cyclohexyl}-carbamicacid tert-butyl ester

The title intermediate (3.1 g, 7.7 mmol, 77%) was obtained as a whitesolid from trans-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester(2.73 g, 12.0 mmol) and 4-bromo-3-fluoro-aniline (1.90 g, 10.0 mmol)analogously to Intermediate 75.7. HPLC: ^(G)t_(Ret)=8.221 min; LC-MS:m/z 401.3 [M+H]⁺.

Example 178(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[(S)-1-(2-oxo-piperazin-1-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one

The title compound (665 mg, 1.19 mmol, 85%) was obtained as a yellowsolid from Intermediate 178.1 (910 mg, 1.40 mmol) analogously to Example51. HPLC: ^(E)t_(Ret)=4.449 min; LC-MS: m/z 549.2 [M+H]⁺.

Intermediate 178.1:4-((S)-1-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-3-oxo-piperazine-1-carboxylicacid tert-butyl ester

The title intermediate (910 mg, 1.4 mmol, 26%) was obtained as a yellowsolid from Intermediate 75.6 (1.87 g, 5.41 mmol) and Intermediate 178.2(2.39 g, 5.57 mmol) analogously to Example 75. HPLC: ^(E)t_(Ret)=5.677min; LC-MS: m/z 648.2 [M+H]⁺.

Intermediate 178.2:4-[(S)-1-(4-Iodo-phenyl)-ethyl]-3-oxo-piperazine-1-carboxylic acidtert-butyl ester

To a solution of Intermediate 178.3 (3.58 g, 7.67 mmol) in THF (27.1 mL)was added 60% NaH (0.32 g, 8.05 mmol) at 0° C. under an argonatmosphere. The reaction mixture was stirred for 2 h at RT. The reactionmixture was quenched with water at 0° C. and extracted with EtOAc. Theorganic phase was washed with a saturated aqueous solution of NaHCO₃,dried (Na₂SO₄), filtered and concentrated. The residue was purified bycolumn chromatography to afford the title compound (3.29 g, 7.49 mmol,98%) as a beige solid. HPLC: ^(E)t_(Ret)=5.516 min; LC-MS: m/z 431.1[M+H]⁺.

Intermediate 178.3:(2-{(2-Chloro-acetyl)-[(S)-1-(4-iodo-phenyl)-ethyl]-amino}-ethyl)-carbamicacid tert-butyl ester

To a solution of Intermediate 178.4 (4.0 g, 10.25 mmol), Et₃N (4.26 mL,30.7 mmol) and DMAP (25 mg, 0.20 mmol) in DCM (27.1 mL) was added dropwise chloroacetyl chloride (0.86 mL, 10.7 mmol) at 0° C. under an argonatmosphere. The reaction mixture was stirred for 5 h at RT. The reactionmixture was quenched with water at 0° C. and extracted with EtOAc. Theorganic phase was washed with a saturated aqueous solution of NaHCO₃,dried (Na₂SO₄), filtered and concentrated. The residue was purified bycolumn chromatography to afford the title compound (3.59 g, 7.69 mmol,75%) as a white solid. HPLC: ^(E)t_(Ret)=5.461 min; LC-MS: m/z 466.8[M+H]⁺.

Intermediate 178.4:{2-[(S)-1-(4-Iodo-phenyl)-ethylamino]-ethyl}-carbamic acid tert-butylester

A suspension of Intermediate 178.5 (5.45 g, 22.0 mmol),(2-Bromo-ethyl)-carbamic acid tert-butyl ester (6.43 g, 28.7 mmol),K₂CO₃ (6.1 g, 44.1 mmol) and KI (0.18 g, 1.1 mmol) in tert-BuOH (25 mL)was heated at 60° C. under an argon atmosphere during two overnight. Thereaction mixture was allowed to cool down and diluted with iso-PrOH. Themixture was filtered and the filter cake washed with iso-PrOH. Thefiltrate was evaporated and partitioned between EtOAc and saturatedNaHCO₃ aqueous solution. The aqueous layer was extracted twice withEtOAc. The combined organic layers were washed with brine, dried overMgSO₄, filtered and evaporated to give a brown solid, which was purifiedby column chromatography to afford the title compound (4.0 g, 10.25mmol, 46.5%) as an white solid. HPLC: ^(E)t_(Ret)=4.489 min; LC-MS: m/z390.93 [M+H]⁺.

Intermediate 178.5: (S)-1-(4-Iodo-phenyl)-ethylamine

Intermediate 178.5 (13.7 g, 55.4 mmol, 76%) was synthesized from(S)-1-phenyl-ethylamine by following the reported methods in Journal ofMedicinal Chemistry, 2001, 44, pp 21. HPLC: ^(E)t_(Ret)=3.639 min;LC-MS: m/z 247.8 [M+H]⁺.

Example 179(S)-1-(4-Chloro-phenyl)-2-(4-{(S)-1-[4-(2-hydroxy-ethyl)-2-oxo-piperazin-1-yl]-ethyl}-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To a solution of Example 178 (30 mg, 0.055 mmol) in EtOH (0.8 mL) wassuccessively added Et₃N (18.97 μl, 0.137 mmol) and 2-bromoethanol (5.41μl, 0.077 mmol). The mixture was irradiated to 105° C. for 12 h. Aftercooling, the mixture was evaporated to dryness. The residue was directlypurified by Combi-Flash Companion™ (Isco Inc.) column chromatography(SiO₂; gradient elution, DCM/[DCM/EtOH/NH₃ aq 90: 9:1] 1:0→0:1)) toyield the title compound (17 mg, 0.029 mmol, 53%) as a pale yellow foam.HPLC: ^(F)t_(Ret)=0.936; LC-MS: m/z 592.5 [M+H]⁺.

Example 180(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[(R)-1-(2-oxo-piperazin-1-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one

The title compound (75 mg, 0.138 mmol, 64%) was obtained as a paleyellow foam analogously to Example 178, starting fromR-(+)-1-(4-bromophenyl)ethylamine. HPLC: ^(F)t_(Ret)=0.922; LC-MS: m/z548.5 [M+H]⁺.

Example 181(S)-1-(4-Chloro-phenyl)-2-(4-{(R)-1-[4-(2-hydroxy-ethyl)-2-oxo-piperazin-1-yl]-ethyl}-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (25.5 mg, 0.043 mmol, 52.5%) was obtained fromExample 180 as a yellow solid analogously to Example 179. HPLC:^(F)t_(Ret)=0.932; LC-MS: m/z 592.5 [M+H]⁺.

Example 183(S)-1-(4-Chloro-phenyl)-2-{4-[(3-hydroxy-3-hydroxymethyl-cyclobutyl-methyl)-methyl-amino]-phenyl}-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (39 mg, 0.07 mmol, 16%) was obtained as a pale yellowfoam from Intermediate 183.1 (200 mg, 0.434 mmol) and Intermediate 75.6(150 mg, 0.434 mmol) analogously to Example 75. HPLC: ^(F)t_(Ret)=1.098;LC-MS: m/z 565.5 [M+H]⁺

Intermediate 183.1:3-{[(4-Bromo-phenyl)-methyl-amino]-methyl}-1-hydroxymethyl-cyclobutanol

To a solution of Intermediate 183.2 (561 mg, 1.785 mmol) in THF (15 mL)was added drop wise at RT borane-methyl sulfide complex (0.802 ml, 8.03mmol). The mixture was then heated at 45° C. for 5 h. After cooling toRT, the suspension was diluted with THF and quenched at 0° C. with MeOH.The solvent were removed by evaporation and the residue was diluted withEtOH (5 mL) and 1M NaOH (10 mL) and heated to reflux for 2 h. Aftercooling to RT and filtration, the filtrate was concentrated and theresidue partitioned between H₂O and EtOAC. After separation, the aqueousphase was re-extracted twice with EtOAc. The combined organic extractswere washed with saturated brine, dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution, DCM/[DCM/EtOH/NH3 aq 90:9:1] 1:0→0:1)) to yield the titleintermediate (467 mg, 1.558 mmol, 87%) as a cis/trans mixture of palebeige crystalline solid, HPLC: ^(F)t_(Ret)=0.854/0.871; LC-MS: m/z 300.2[M+H]⁺

Intermediate 183.2: 3-Hydroxy-3-hydroxymethyl-cyclobutanecarboxylic acid(4-bromo-phenyl)-methyl-amide

To a suspension of AD-Mix-Alpha (2.748 g, 1.963 mmol) in a mixture oftBuOH (10 mL) and H₂O (10 mL) was added at 5° C. Intermediate 183.3 (500mg, 1.785 mmol) as a concentrated tBuOH solution. The cooling bath wasremoved and the mixture stirred at RT for 1 h then filtered. Thefiltrate was concentrated under vacuum and the remaining aqueous phaseextracted four times with DCM. The combined organic extracts were washedwith saturated brine, dried over Na₂SO₄, filtered and evaporated todryness to yield the title intermediate as an oil (586 mg, 1.865 mmol).HPLC: ^(F)t_(Ret)=0.797; LC-MS: m/z 314.2 [M+H]⁺.

Intermediate 183.3: 3-Methylene-cyclobutanecarboxylic acid(4-bromo-phenyl)-methyl-amide

To a solution of Intermediate 183.4 (1.748 g, 15.59 mmol) in DCM (30 mL)was successively added at 0° C., three drops of DMF and oxalyl chloride(1.433 ml, 16.37 mmol). The ice bath was removed and the mixture stirredfor 2 h at RT. Volatiles were evaporated, the pale yellow oil driedunder vacuum and then dissolved in DCM. To this solution was added at 0°C., a solution of 4-bromo-N-methylaniline (2.90 g, 15.59 mmol), Et₃N(6.48 mL, 46.8 mmol) and DMAP (1.904 g, 15.59 mmol) in DCM (30 mL).After addition, the ice bath was removed and the mixture stirred at RTfor 1 h. The reaction mixture was then quenched with H₂O and NaHCO₃, andpartitionned between DCM and H₂O. After separation, the aqueous phasewas re-extracted twice with DCM and the combined organic extracts werewashed with saturated brine, dried over Na₂SO₄, filtered and evaporatedto dryness. The resulting crude material was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elution,DCM/[DCM/EtOH 9:1] 1:0→1:1)) to yield the title intermediate (3.36 g,12.02 mmol, 77%) as a pale yellow oil. HPLC: ^(F)t_(Ret)=1.232; LC-MS:m/z 280.2 [M+H]⁺.

Intermediate 183.4: 3-Methylene-cyclobutanecarboxylic acid

3-methylenecyclobutanecarbonitrile (5 g, 53.7 mmol) was added to asolution of NaOH (15.33 g, 383 mmol) in H₂O (51 mL). The biphasicmixture was heated to reflux for 3 h. After cooling to RT, the mixturewas acidified by addition of 32% HCl and saturated with NaCl. Theaqueous phase was extracted six time with DCM. The combined organicextracts were washed with saturated brine, dried over Na₂SO₄, filteredand evaporated to dryness to yield the title intermediate (6.01 g, 53.6mmol, 100%) as an oil. HPLC: ^(F)t_(Ret)=0.673; LC-MS: m/z 111.1 [M−H]⁻.

Intermediate 184.1:2-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-5-methyl-3-oxo-hexanenitrile

To a mixture of Intermediate 164.2 (102 mg, 0.22 mmol) and isovalerylchloride (0.12 mL, 0.98 mmol) in DMF (2.0 mL) was added 60% of NaH inmineral oil (11 mg, 0.275 mmol) at 0° C. (ice bath). The resultingmixture was stirred at RT for 1 h, AcOH was carefully added to quenchthe reaction and the mixture was extracted with AcOEt (2×). The combinedorganic fractions were dried over Na₂SO₄, filtered and evaporated todryness. The resulting crude material was purified by columnchromatography to yield the title intermediate (120 mg, 0.22 mmol,100%). HPLC: ^(G)t_(Ret)=8.00 min; LC-MS: m/z 545.43 [M+H]⁺.

Intermediate 185.1:4-{5-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-2-yl}-3,5-dimethyl-pyrazole-1-carboxylicacid tert-butyl ester

The title intermediate (233 mg, 0.38 mmol, 63%) was obtained as a yellowsolid from Intermediate 185.2 (300 mg, 0.60 mmol) and3,5-Dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (212 mg, 0.66 mmol) analogously to Example 36.LC-MS: m/z 617.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) 1.18-1.30 (m, 6H),1.58 (s, 9H), 2.24 (s, 3H), 2.73 (s, 3H), 3.71 (s, 1H), 3.74 (s, 3H),3.92 (s, 1H), 4.40-4.50 (m, 1H), 6.25 (s, 1H), 6.89 (s, 1H), 7.06 (s,1H), 7.39 (s, 3H), 7.48 (d, J=8.59 Hz, 1H), 7.70 (d, J=11.32 Hz, 1H),7.95 (s, 1H), 8.51 (d, J=3.51 Hz, 1H).

Intermediate 185.2:2-(6-Bromo-pyridin-3-yl)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (607 mg, 1.21 mmol, 18.5%) was obtained as awhite solid from Intermediate 185.3 (1.93 g, 6.53 mmol) and Intermediate96.1 (1.95 g, 8.00 mmol) analogously to Example 1. HPLC:^(E)t_(Ret)=5.526 min; LC-MS: m/z 502.7 [M+H]⁺.

Intermediate 185.3:(6-Bromo-pyridin-3-yl)-[1-(4-chloro-phenyl)-meth-(E)-ylidene]-amine

The title compound (1.93 g, 6.53 mmol, 83%) was obtained as a orangesolid from 6-Bromo-pyridin-3-ylamine (1.36 g, 7.89 mmol) and4-chloro-benzaldehyde (1.38 g, 9.86 mmol) analogously to Intermediate1.4. ¹H NMR (400 MHz, DMSO-d₆) 7.61 (d, 2H), 7.69 (d, 2H), 7.95 (d, 2H),8.30-8.35 (m, 1H), 8.71 (s, 1H).

Example 1861-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(2-methoxy-4-methyl-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

A mixture of Intermediate 186.1 (33 mg, 0.078 mmol), 2-iodopropane(0.023 mL, 0.234 mmol) and Cs₂CO₃ (50.7 mg, 0.156 mmol) in DMF (0.5 mL)was stirred for 1 h at 50° C. The reaction mixture was allowed to coolto RT, quenched by addition of a saturated aqueous solution of NaHCO₃and extracted with AcOEt. The organic phase was washed with a saturatedaqueous solution of NaHCO₃, dried (Na₂SO₄), filtered and concentrated.The residue was purified by column chromatography (SiO₂; DCM/MeOH 99:1)to afford 33 mg of the title compound as a white solid. TLC: R_(F)=0.88(DCM/MeOH 9:1); HPLC: ^(L)t_(Ret)=5.74 min; LC-MS: m/z 466.4 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d6): 1.06-1.25 (m, 6H) 2.25 (s, 3H) 2.41-2.52 (m, 6H)3.54 (d, 1H) 3.92 (d, 1H) 4.31-4.50 (m, 1H) 5.69 (br, 1H) 6.46-6.97 (m,5H) 7.29 (br, 4H).

Intermediate 186.1:1-(4-Chloro-phenyl)-7-hydroxy-6-methoxy-2-(2-methoxy-4-methyl-phenyl)-1,4-dihydro-2H-isoquinolin-3-one

To solution of Intermediate 187.3 (375 mg, 0.818 mmol) in DCM (10 mL)was added a solution of Intermediate 186.2 (276 mg, 1.06 mmol) in DCM (5mL) at 0° C. and under an argon atmosphere. The reaction mixture wasstirred for 1 h at RT and cooled to 0° C. Trifluoromethane sulfonic acid(0.291 mL, 3.27 mmol) was added. The resulting mixture was stirred 1 hat 0° C., quenched by addition of a saturated aqueous solution of NaHCO₃and extracted with DCM. The organic phase was washed with a saturatedaqueous solution of NaHCO₃, dried (Na₂SO₄), filtered and concentrated.The residue was purified by column chromatography (SiO₂; DCM/MeOH100:0→98:2) followed by trituration in AcOEt to afford 35 mg of thetitle compound as a white solid. TLC: R_(F)=0.71 (DCM/MeOH 9:1); HPLC:^(L)t_(Ret)=4.77 min; LC-MS: m/z 424.3 [M+H]⁺.

Intermediate 186.2:[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-(2-methoxy-4-methyl-phenyl)-amine

A mixture of Intermediate 186.3 (1.57 g, 11.4 mmol), and4-chlorobenzaldehyde (1.63 g, 11.4 mmol) and acetic acid (0.66 mL, 11.4mmol) was stirred for 18 h at 85° C., allowed to cool to RT andconcentrated to afford 3.25 g of the title compound as an brown oilwhich was used as a crude material. ¹H NMR (400 MHz, DMSO-d₆) 2.32 (s,3H), 3.78 (s, 3H), 6.77 (d, J=7.82 Hz, 1H), 6.90 (s, 1H), 6.97 (d,J=7.82 Hz, 1H), 7.57 (d, J=8.60 Hz, 2H), 7.91 (d, J=8.60 Hz, 2H), 8.54(s, 1H).

Intermediate 186.3: 2-Methoxy-4-methyl-phenylamine

A mixture of 5-methyl-2-nitroanisole (2 g, 12 mmol) and Raney nickel(2.2 g) in MeOH/THF (120 mL, 3:1 v/v) was shaken for 20 h at RT andunder 0.1 bar of H₂. The reaction mixture was filtered through a pad ofcelite and the filtrate was concentrated to afford 1.57 g of the titlecompound as colorless oil. HPLC: ^(L)t_(Ret)=1.44 min; LC-MS: m/z 138.1[M+H]⁺.

Example 1871-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-[4-methyl-2-(2H-tetrazol-5-ylmethoxy)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

A mixture of Intermediate 187.1 (500 mg, 1.02 mmol), sodium azide (199mg, 3.06 mmol) and ammonium chloride (163 mg, 3.06 mmol) in DMF (4 mL)was stirred for 3 h at 100° C., allowed to cool to RT, quenched byaddition of a saturated aqueous solution of NaCl and extracted withAcOEt. The organic phase was washed with a saturated aqueous solution ofNaCl, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by column chromatography (SiO₂; DCM/MeOH 99:1→94:6) to afford257 mg of the title compound as a yellow solid. TLC: R_(F)=0.32(DCM/MeOH 9:1); HPLC: ^(L)t_(Ret)=5.20 min; LC-MS: m/z 534.4 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d6): 1.04-1.23 (m, 6H) 2.24 (s, 3H) 3.53 (d, 1H) 3.69(s, 3H) 3.91 (d, 1H) 4.29-4.43 (m, 1H) 5.42 (br, 2H) 5.83 (br, 1H)6.59-6.86 (m, 4H) 7.07 (br, 1H) 7.18-7.37 (m, 4H).

Intermediate 187.1:{2-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-5-methyl-phenoxy}-acetonitrile

A mixture of Intermediate 187.2 (1.1 g, 2.52 mmol), 2-iodopropane (0.75mL, 7.55 mmol) and Cs₂CO₃ (1.6 g, 5.03 mmol) in DMF (20 mL) was stirredfor 2 h at 50° C. under an argon atmosphere. The reaction mixture wasallowed to cool to RT, quenched by addition of a saturated aqueoussolution of NaHCO₃ and extracted with AcOEt. The organic phase waswashed with a saturated aqueous solution of NaHCO₃, dried (Na₂SO₄),filtered and concentrated. The residue was purified by columnchromatography (SiO₂; DCM/MeOH 100:0→98:2) to afford 1.1 g of the titlecompound as a white solid. TLC: R_(F)=0.81 (DCM/MeOH 9:1); HPLC:^(L)t_(Ret)=5.45 min; LC-MS: m/z 491.4 [M+H]⁺.

Intermediate 187.2:{2-[1-(4-Chloro-phenyl)-7-hydroxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-5-methyl-phenoxy}-acetonitrile

To solution of Intermediate 187.3 (2.3 g, 7.27 mmol) in DCM (50 mL) wasadded a solution of Intermediate 187.7 (2.7 g, 9.45 mmol) in DCM (5 mL)at 0° C. and under an argon atmosphere. The reaction mixture was stirredfor 1 h at RT and cooled to 0° C. Trifluoromethane sulfonic acid (2.6mL, 29.1 mmol) was added. The resulting mixture was stirred 1 h at 0°C., quenched by addition of a saturated aqueous solution of NaHCO₃ andextracted with DCM. The organic phase was washed with a saturatedaqueous solution of NaHCO₃, dried (Na₂SO₄), filtered and concentrated.The residue was purified by column chromatography (SiO₂; DCM/MeOH100:0→98:2) followed by trituration in AcOEt to afford 1.2 g of thetitle compound as a white solid. TLC: R_(F)=0.57 (DCM/MeOH 9:1); HPLC:^(L)t_(Ret)=4.57 min; LC-MS: m/z 449.3 [M+H]⁺.

Intermediate 187.3: [3-Methoxy-4-(4-methoxy-benzyloxy)-phenyl]-acetylchloride

To a cold (0° C.) solution of Intermediate 187.4 (2.2 g, 7.26 mmol) inDCM (50 mL) was added 1-chloro-N,N,2-trimethyl-1-propenyl-amine (1.2 mL,8.71 mmol), under an argon atmosphere. The reaction mixture was stirredfor 30 min at 0° C. and concentrated to afford 3 g of the title compoundas a colorless oil which was immediately used. HPLC: ^(L)t_(Ret)=5.04min (Methyl ester after quenching by MeOH).

Intermediate 187.4: [3-Methoxy-4-(4-methoxy-benzyloxy)-phenyl]-aceticacid

To a stirred solution of Intermediate 187.5 (8.5 g, 25.6 mmol) in THF(50 mL) was added LiOH (2.2 g, 51.3 mmol) in H₂O (25 mL). The reactionmixture was stirred for 16 h at RT, concentrated, diluted with H₂O (50mL) and acidified to pH 1. The resulting precipitate was collected byfiltration to provide 7.1 g of the title compound as a white solid.HPLC: ^(L)t_(Ret)=4.26 min; LC-MS: m/z 320.3 [M+18]⁺.

Intermediate 187.5: [3-Methoxy-4-(4-methoxy-benzyloxy)-phenyl]-aceticacid ethyl ester

A mixture of Intermediate 187.6 (5.6 g, 26.7 mmol), 4-methoxybenzylchloride (4.4 mL, 32.1 mmol) and K₂CO₃ (4.8 g, 34.8 mmol) in DMF (40 mL)was stirred for 30 min at 100° C., allowed to cool to RT, quenched byaddition of a saturated aqueous solution of NaHCO₃ and extracted withDCM. The organic phase was washed with a saturated aqueous solution ofNaHCO₃, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by column chromatography (SiO₂; gradient elution, hexane/AcOEt95:5→75:25) to yield 8.5 g of the title compound as a white solid. TLC:R_(F)=0.76 (hexane/AcOEt 1:1). HPLC: ^(L)t_(Ret)=5.32 min; ¹H NMR (400MHz, DMSO-d₆) 1.16 (t, J=7.04 Hz, 3H), 3.54 (s, 2H), 3.71 (s, 3H), 3.73(s, 3H), 4.05 (q, J=7.30 Hz, 2H), 4.94 (s, 2H), 6.72 (dd, J=8.21, 1.96Hz, 1H), 6.86 (d, J=1.96 Hz, 1H), 6.89-6.98 (m, 3H), 7.34 (d, J=8.60 Hz,2H).

Intermediate 187.6: (4-Hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester

A mixture of homovanillic acid (5 g, 27.4 mmol) and H₂SO₄ (96%, 1.46 mL,27.4 mmol) in EtOH (100 mL) was stirred for 1 h at 85° C., allowed tocool to RT and concentrated. The residue was diluted in H₂O andextracted with DCM. The organic phase was washed with H₂O, dried(Na₂SO₄), filtered and concentrated to afford 5.8 g of the titlecompounds as a yellow oil. LC-MS: m/z 211.2 [M+H]⁺.

Intermediate 187.7:(2-{[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-amino}-5-methyl-phenoxy)-acetonitrile

A mixture of Intermediate 187.8 (1.5 g, 9.25 mmol) and4-chlorobenzaldehyde (1.3 g, 9.25 mmol) in EtOH (20 mL) was stirred for18 h at 85° C., allowed to cool to RT and concentrated to afford 2.7 gof the title compound as a red oil which was used as a crude material.¹H NMR (400 MHz, DMSO-d₆) 2.32 (s, 3H), 5.18 (s, 2H), 6.93 (d, J=7.82Hz, 1H), 7.02 (s, 1H), 7.08 (d, J=7.82 Hz, 1H), 7.57 (dd, 2H), 7.92 (dd,2H), 8.55 (s, 1H).

Intermediate 187.8: (2-Amino-5-methyl-phenoxy)-acetonitrile

A mixture of Intermediate 187.9 (6.3 g, 22.5 mmol) and TFA (17.3 mL, 225mmol) in DCM (50 mL) was stirred for 1 h at RT, quenched by addition ofa saturated aqueous solution of NaHCO₃ and extracted with DCM. Theorganic phase was washed with a saturated aqueous solution of NaHCO₃,dried (Na₂SO₄), filtered and concentrated. The residue was purified bycolumn chromatography (SiO₂; hexane/AcOEt 95:5→80:20) to yield 1.5 g ofthe title compound as an orange solid. TLC: R_(F)=0.6 (hexane/AcOEt1:1); HPLC: ^(L)t_(Ret)=1.43 min; LC-MS: m/z 163.1 [M+H]⁺.

Intermediate 187.9: (2-Cyanomethoxy-4-methyl-phenyl)-carbamic acidtert-butyl ester

A mixture of Intermediate 187.10 (5 g, 22.4 mmol), K₂CO₃ (9.3 g, 67.2mmol) and bromoacetonitrile (2.2 mL, 33.6 mmol) in DMF (50 mL) wasstirred for 1 h at RT, quenched by addition of a saturated aqueoussolution of NaHCO₃ and extracted with AcOEt. The organic phase waswashed with a saturated aqueous solution of NaHCO₃, dried (Na₂SO₄),filtered and concentrated to afford 6.3 g of the title compound as ablack oil which was used as a crude material. HPLC: ^(L)t_(Ret)=5.21min; LC-MS: m/z 261.3 [M−H]⁻.

Intermediate 187.10: (2-Hydroxy-4-methyl-phenyl)-carbamic acidtert-butyl ester

To a stirred solution of 6-amino-m-cresol (5 g, 40.6 mmol) in DCM (100mL) was added di-tert-butyl carbonate (9.4 ml, 40.6 mmol), under anargon atmosphere. The resulting mixture was stirred for 18 h at RT,quenched by addition of a saturated aqueous solution of NaHCO₃ andextracted with DCM. The organic phase was washed with a saturatedaqueous solution of NaHCO₃, dried (Na₂SO₄), filtered and concentrated toafford 9.1 g of the title compound as a black oil which was used as acrude material. HPLC: ^(L)t_(Ret)=4.86 min; LC-MS: m/z 224.3 [M+H]⁺.

Example 1881-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-[4-methyl-2-(thiazol-5-ylmethoxy)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

To solution of Intermediate 187.3 (773 mg, 2.23 mmol) in DCM (10 mL) wasadded a solution of Intermediate 188.1 (841 mg, 2.452 mmol) in DCM (5mL) and under an argon atmosphere. The reaction mixture was stirred for1 h at RT and cooled to 0° C. Trifluoromethane sulfonic acid (0.291 mL,3.27 mmol) was added. The resulting mixture was stirred 10 min at 0° C.,quenched by addition of a saturated aqueous solution of NaHCO₃ andextracted with DCM. The organic phase was washed with a saturatedaqueous solution of NaHCO₃, dried (Na₂SO₄), filtered and concentrated.The residue was purified by column chromatography (SiO₂; gradientelution, DCM/MeOH 100:0→98:2) followed by trituration in AcOEt to afford400 mg of the title compound as a white solid. TLC: R_(F)=0.42 (DCM/MeOH9:1); LC-MS: m/z 549.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): 1.00-1.32 (m,6H) 2.26 (s, 3H) 3.54 (d, 1H) 3.71 (s, 3H) 3.84-4.00 (m, 1H) 4.28-4.45(m, 1H) 5.12-5.49 (m, 2H) 5.63 (br, 1H) 6.47-6.87 (m, 4H) 6.95-7.45 (m,5H) 7.83 (s, 1H) 9.00 (br, 1H).

Intermediate 188.1:[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-[4-methyl-2-(thiazol-5-yl-methoxy-phenyl)-amine

A mixture of Intermediate 188.2 (815 mg, 3.70 mmol), and4-chlorobenzaldehyde (472 mg, 3.70 mmol) and acetic acid (0.21 ml, 3.70mmol) was stirred for 18 h at 85° C., allowed to cool to RT andconcentrated to afford 1.39 g of the title compound as a black oil whichwas used as a crude material. ¹H NMR (400 MHz, DMSO-d6) 1.00-1.32 (m,6H), 2.26 (s, 3H), 3.54 (d, 1H), 3.71 (s, 3H), 3.84-4.00 (m, 1H),4.28-4.45 (m, 1H), 5.12-5.49 (m, 2H), 5.63 (br, 1H), 6.47-6.87 (m, 4H),6.95-7.45 (m, 5H), 7.83 (s, 1H), 9.00 (br, 1H).

Intermediate 188.2: 4-Methyl-2-(thiazol-5-ylmethoxy)-phenylamine

A mixture of Intermediate 188.3 (935 mg, 3.74 mmol) and Raney nickel(400 mg) in MeOH/THF (40 mL, 3:1 v/v) was shaken for 27.5 h at RT, under0.1 bar of H₂. The reaction mixture was filtered through a pad of celiteand the filtrate was concentrated. The residue was purified by columnchromatography (SiO₂; DCM/MeOH 100:0→98:2) to afford 815 mg of the titlecompound as a red oil. TLC: R_(F)=0.6 (DCM/MeOH 9:1); HPLC:^(L)t_(Ret)=1.76 min; LC-MS: m/z 221.2 [M+H]⁺.

Intermediate 188.3: 5-(5-Methyl-2-nitro-phenoxymethyl)-thiazole

To a solution of 5-(hydroxymethyl)-1,3-thiazole (1 g, 8.68 mmol) in DMF(15 mL) was added NaH (0.413 g, 9.47 mmol) under an argon atmosphere.The reaction mixture was stirred for 20 min at 0° C.3-Fluoro-4-nitrotoluene (1.2 g, 7.89 mmol) was added. The resultingmixture was stirred for 1 h at RT, quenched by addition of a saturatedaqueous solution of NaHCO₃ and extracted with AcOEt. The organic phasewas washed with a saturated aqueous solution of NaHCO₃, dried (Na₂SO₄),filtered and concentrated. The residue was purified by columnchromatography (SiO₂; hexane/AcOEt 60:40→40:60) to afford 936 mg of thetitle compound as an orange solid. TLC: R_(F)=0.35 (hexane/AcOEt 1:1);HPLC: ^(L)t_(Ret)=4.26 min; LC-MS: m/z 251.2 [M+H]⁺.

Example 1894-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-(2H-tetrazol-5-ylmethoxy)-benzoicacid methyl ester

The title compound (132.4 mg, 0.208 mmol) was obtained as an off-whitesolid from Intermediate 189.1 (398 mg, 0.744 mmol) analogously toExample 187. HPLC: ^(M)t_(Ret)=1.10 min; LC-MS: m/z 578.2 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d6): 1.14 (d, J=5.85 Hz, 3H) 1.20 (d, J=5.85 Hz, 3H)3.57-3.63 (m, 1H) 3.73 (s, 3H) 3.85 (s, 3H) 3.96 (d, J=19.98 Hz, 1H)4.38 (dt, J=11.96, 6.03 Hz, 1H) 5.35-5.72 (m, 2H) 5.95 (br. s., 1H) 6.73(s, 1H) 6.83 (s, 1H) 6.89-7.20 (m, 1H) 7.20-7.39 (m, 4H) 7.54 (br. s.,1H) 7.80 (br. s., 1H) 16.76 (br. s., 1H).

Intermediate 189.1:4-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-cyanomethoxy-benzoicacid methyl ester

The title intermediate (298.9 mg, 0.559 mmol) was obtained as anoff-white solid from Intermediate 189.2 (398 mg, 0.744 mmol) analogouslyto intermediate 187.9. HPLC: ^(M)t_(Ret)=1.17 min; LC-MS: m/z 535[M+H]⁺.

Intermediate 189.2:4-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-hydroxy-benzoicacid methyl ester

The title intermediate (296 mg, 0.597 mmol) was obtained as an off-whitesolid from Intermediate 189.3 (331 mg, 0.0.542 mmol) using a 1M TBAFsolution in THF and the reaction was stirred for 45 minutes at roomtemperature. After workup, the title compound was obtained as a yellowsolid. HPLC: ^(M)t_(Ret)=1.13 min; LC-MS: m/z 496 [M+H]⁺; ¹H NMR (400MHz, DMSO-d6): 1.09-1.26 (m, 6H) 3.54-3.65 (m, 1H) 3.74 (s, 3H) 3.81 (s,3H) 3.94-4.02 (m, 1H) 4.37-4.50 (m, 1H) 5.88 (s, 2H) 6.81-6.96 (m, 2H)7.22-7.39 (m, 4H) 7.46-7.56 (m, 3H).

Intermediate 189.3:3-(tert-Butyl-dimethyl-silanyloxy)-4-[1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzoicacid methyl ester

The title intermediate (331 mg, 0.542 mmol) was obtained as a whitesolid from Intermediate 96.2 (555 mg, 2.475 mmol) and Intermediate 189.4(1.0 g, 2.475 mmol) analogously to intermediate 187.2. HPLC:^(M)t_(Ret)=1.47 min; LC-MS: m/z 610 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6):−0.17-0.25 (m, 6H) 0.60-0.93 (m, 9H) 1.06-1.27 (m, 6H) 3.51-3.66 (m, 1H)3.69-3.77 (m, 3H) 3.82 (d, J=12.92 Hz, 3H) 3.92-4.13 (m, 1H) 4.34-4.50(m, 1H) 5.66-5.95 (m, 1H) 6.79-7.02 (m, 2H) 7.20-7.61 (m, 7H).

Intermediate 189.4:3-(tert-Butyl-dimethyl-silanyloxy)-4-{[1-(4-chloro-phenyl)-meth-(E)-ylidene]-amino}-benzoicacid methyl ester

The title intermediate (4.75 g, 9.99 mmol) was obtained as a brown solidfrom Intermediate 189.5 (3.37 g, 11.63 mmol) using TBDMS chloride (1.753g, 11.63 mmol), triethylamine (3.24 mL, 23.26 mmol), DMAP (142 mg, 1.163mmol) in 116 mL DCM stirring at room temperature for 15 h. ¹H NMR (400MHz, DMSO-d6): 0.14 (s, 6H) 0.92 (s, 9H) 3.84 (s, 3H) 7.18 (d, J=8.20Hz, 1H) 7.43 (d, J=1.56 Hz, 1H) 7.63 (d, J=8.59 Hz, 3H) 7.96 (d, J=8.20Hz, 2H) 8.58 (s, 1H).

Intermediate 189.5:4-{[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-amino}-3-hydroxy-benzoic acidmethyl ester

The title intermediate (3.37 g, 11.63 mmol) was obtained as an off-whitesolid from chloro benzaldehyde (1.682 g, 11.96 mmol) and methyl4-amino-3hydroxybenzoate (2.0 g, 11.96 mmol) analogously to intermediate187.7. ¹H NMR (400 MHz, DMSO-d6): 3.83 (s, 3H) 7.22 (d, J=8.20 Hz, 1H)7.36-7.54 (m, 2H) 7.61 (d, J=8.59 Hz, 2H) 8.04 (d, J=8.59 Hz, 2H) 8.70(s, 1H) 9.59 (s, 1H).

Example 1904-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-methoxy-benzoicacid methyl ester

The title compound was obtained by reaction of Intermediate 189.2 (200mg, 0.403 mmol) with iodomethane (86 mg, 0.605 mmol) in the presence ofpotassium carbonate (167 mg, 1.21 mmol) in 4 mL DMF at 100° C. for 30min. The reaction mixture was diluted with ethyl acetate and washed withaqueous NaHCO₃ solution and brine. The crude product was purified byautomated normal phase column chromatography (eluting withn-heptane—ethyl acetate), yielding the title compound as a brownishsolid (0.51 g, 0.904 mmol). HPLC: ^(M)t_(Ret)=1.19 min; LC-MS: m/z 510.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): 1.14 (d, J=5.85 Hz, 3H) 1.22 (d,J=5.85 Hz, 3H) 3.61 (d, J=19.98 Hz, 1H) 3.66-3.93 (m, 9H) 3.99 (d,J=19.98 Hz, 1H) 4.36-4.48 (m, 1H) 5.83 (br. s., 1H) 6.86 (s, 2H)6.92-7.69 (m, 7H).

Example 1914-[1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-3-(thiazol-5-ylmethoxy)-benzoicacid methyl ester

The title compound was obtained by reaction of Intermediate 189.2 (400mg, 0.807 mmol) with 5-(hydroxymethyl)-1,3,thiazole (139 mg, 1.210 mmol)in the presence of di-tert-butylazodicarboxylate (279 mg, 1.21 mmol) andtriphenylphosphine in 8 mL dry DCM at room temperature for 19 h. Thereaction mixture was concentrated in vacuo and the crude product waspurified by automated normal phase column chromatography (eluting withn-heptane—ethyl acetate), yielding the title compound as a colorless oil(0.375 g, 0.518 mmol). HPLC: ^(M)t_(Ret)=1.15 min; LC-MS: m/z 593.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): 1.15 (d, J=5.85 Hz, 3H) 1.21 (d,J=6.06 Hz, 3H) 3.58-3.64 (m, 1H) 3.74 (s, 3H) 3.86 (s, 3H) 3.89-4.06 (m,1H) 4.34-4.44 (m, 1H) 5.47 (br. s., 2H) 5.80 (br. s., 1H) 6.80 (s, 1H)6.86 (s, 1H) 7.26 (br. s., 4H) 7.42-7.83 (m, 3H) 7.87 (s, 1H) 9.04 (br.s., 1H).

Intermediate 192.1:(S)-2-[4-((S)-1-Amino-ethyl)-phenyl]-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title compound (1.28 g, 2.75 mmol, 100%) was obtained as a solidfrom Intermediate 192.2 (1.55 g, 2.74 mmol) analogously to Example 51.HPLC: ^(K)t_(Ret)=5.99 min; LC-MS: m/z 465.4 [M+H]⁺.

Intermediate 192.2:((S)-1-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-ethyl)-carbamicacid tert-butyl ester

The title intermediate (1.61 g, 2.85 mmol, 49.3%) was obtained as awhite solid from Intermediate 75.6 (2.0 g, 5.78 mmol) and Intermediate192.3 (2.0 g, 5.78 mmol) analogously to Example 75. HPLC:^(K)t_(Ret)=7.55 min; LC-MS: m/z 582.5 [M+NH4]⁺.

Intermediate 192.3: [(S)-1-(4-Iodo-phenyl)-ethyl]-carbamic acidtert-butyl ester

To a mixture of Intermediate 178.5 (5.0 g, 20.2 mmol) and Et₃N (5.64 mL,40.5 mmol) in DCM (35 mL) was added di-tert-butyl dicarbonate (5.3 g,24.3 mmol). After stirring for 1 h at RT, it was quenched by addition ofa saturated aqueous solution of NH₄Cl and extracted with DCM. Theorganic phase was washed with a saturated aqueous solution of NaHCO₃,dried (Na₂SO₄), filtered and concentrated. The residue was purified bycolumn chromatography (SiO₂; hexane/AcOEt 90:10) to yield (6.27 g, 18.1mmol, 89%) of the title compound as a white solid. HPLC:^(K)t_(Ret)=7.35 min; LC-MS: m/z 365.2 [M+NH4]⁺.

Example 195(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(2-oxo-pyrrolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (28 mg, 0.044 mmol, 15%) was obtained as a yellowfoam from Intermediate 75.6 (100 mg, 0.289 mmol) and Intermediate 195.1(120 mg, 0.289 mmol), analogously to Example 130. HPLC: ^(D)t_(Ret)=1.05min; LC-MS: m/z 631.5 [M+H]⁺.

Intermediate 195.1:1-(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-pyrrolidin-2-one

To the mixture of Intermediate 195.2 (1.31 g, 2.91 mmol), potassiumcarbonat (9.26 g, 67.0 mmol) and acetone (150 mL) was added potassiumiodide (1.015 g, 6.12 mmol). The mixture was stirred for 48 h at refluxtemperature. The reaction mixture was concentrated and the residue wasextracted between EtOAc (2×) and 1M aqueous NaHCO₃ (1×). The organicphases were washed with brine and dried over Na₂SO₄, filtered andevaporated to dryness. The residue was crystallized (iPrOH) to affordthe title compound as beige crystals (769 mg, 1.71 mmol, 59%). HPLC:^(J)t_(Ret)=2.95 min; LC-MS: m/z 414.3 [M+H]⁺.

Intermediate 195.2:4-Chloro-N-(4-{[(5-iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-butyramide

To the stirred solution of Intermediate 130.4 (1.0 g, 2.90 mmol),triethylamine (0.803 mL, 5.79 mmol) and chloroform (30 mL) was addeddrop wise 4-chloro-butyryl chloride. The mixture was stirred for 1 h atRT. The reaction mixture was extracted between DCM (2×) and 1M aqueousNaHCO₃ (1×). The organic phases were washed with brine and dried overNa₂SO₄, filtered and evaporated to dryness. The residue was crystallized(DCM-hexane) to afford the title compound as beige crystals (1.30 g,2.90 mmol, 99%). HPLC: ^(J)t_(Ret)=4.26 min; LC-MS: m/z 450.3 [M+H]⁺.

Example 196(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(2-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (61 mg, 0.096 mmol, 33%) was obtained as a yellowfoam from Intermediate 75.6 (100 mg, 0.289 mmol) and Intermediate 196.1(120 mg, 0.289 mmol), analogously to Example 130. HPLC: ^(D)t_(Ret)=1.12min; LC-MS: m/z 632.6 [M+H]⁺.

Intermediate 196.1:1-(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-imidazolidin-2-one

To the solution of Intermediate 196.2 (295 mg, 0.76 mmol) and THF (30mL) was added CDI (123 mg, 0.76 mmol). The mixture was stirred for 1 hat reflux temperature. The reaction mixture was extracted between EtOAc(2×) and 1M aqueous NaHCO₃ (1×). The organic phases were washed withbrine and dried over Na₂SO₄, filtered and evaporated to dryness. Theresidue was crystallized (EtOAc) to afford the title compound as beigecrystals (204 mg, 0.492 mmol, 64%). HPLC: ^(J)t_(Ret)=3.71 min; LC-MS:m/z 415.3 [M+H]⁺.

Intermediate 196.2:N*1*-(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-ethane-1,2-diamine

To the solution of Intermediate 196.3 (390 mg, 0.80 mmol) and DCM (20mL) was added TFA (1.23 mL, 15.8 mmol). The mixture was stirred for 2 hat RT. The reaction mixture was extracted between DCM (2×) and 1Maqueous NaHCO₃ (1×). The organic phases were washed with brine and driedover Na₂SO₄, filtered and evaporated to dryness, gave the title compoundas a slightly yellow oil (298 mg, 767 mmol, 96%). HPLC: ^(J)t_(Ret)=1.90min; LC-MS: m/z 389.3 [M+H]⁺.

Intermediate 196.3:[2-(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl-amino)-ethyl]-carbamicacid tert-butyl ester

To a solution of Intermediate 130.4 (800 mg, 2.317 mmol),(2-oxo-ethyl)-carbamic acid tert-butyl ester (406 mg, 2.55 mmol) in MeOH(50 mL) was added NaBH₄CN (218 mg, 3.48 mmol) at RT. The mixture wasstirred for 18 h at RT. To the reaction mixture was concentrated and tothe residue was added 1M aqueous NaHCO₃ followed by extraction withEtOAc (2×). The organic phases were dried over Na₂SO₄, filtered andevaporated. Purification of the residue by normal phase columnchromatography, eluting with DCM-MeOH-aq. 30% NH₄OH (200:20:1), gave thetitle compound as slightly yellow oil (398 mg, 0.815 mmol, 35%). HPLC:^(J)t_(Ret)=3.64.

Example 197(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(3-oxo-morpholin-4-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (74 mg, 0.113 mmol, 39%) was obtained as a yellowfoam from Intermediate 75.6 (100 mg, 0.289 mmol) and Intermediate 197.1(124 mg, 0.289), analogously to Example 130. HPLC: ^(J)t_(Ret)=1.15 min;LC-MS: m/z 647.5 [M+H]⁺.

Intermediate 197.1:4-(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-morpholin-3-one

To the stirred solution of Intermediate 197.2 (670 mg, 1.439 mmol) andTHF (100 mL) was added NaH (54.5 mg, 2.158 mmol) at 0° C. The mixturewas stirred for 3 h at 0° C. The reaction mixture was extracted betweenEtOAc (2×) and 1M aqueous NaHCO₃ (1×). The organic phases were washedwith brine and dried over Na₂SO₄, filtered and evaporated to dryness.The residue was purified by normal phase column chromatography, elutingwith EtOAc-hexane (3:1), afforded the title compound aftercrystallization (DCM-hexane) as slightly yellow crystals (254 mg, 0.592mmol, 41%). HPLC: ^(J)t_(Ret)=3.66 min; LC-MS: m/z 430.2 [M+H]⁺.

Intermediate 197.2:2-(2-Chloro-ethoxy)-N-(4-{[(5-iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-acetamide

The title intermediate (670 mg, 1.424 mmol, 98%) was obtained as aslightly yellow oil from Intermediate 130.4 (500 mg, 1.448 mmol) and(2-chloro-ethoxy)-acetyl chloride (227 mg, 1.448 mmol) analogously toIntermediate 195.2. HPLC: ^(J)t_(Ret)=4.40 min; LC-MS: m/z 466.3 [M+H]⁺.

Example 198(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (96 mg, 0.144 mmol, 36%) was obtained as a yellowfoam from Intermediate 198.1 (146 mg, 0.400 mmol) and Intermediate 149.1(50 mg, 0.100 mmol), analogously to Example 130. HPLC: ^(D)t_(Ret)=1.21min; LC-MS: m/z 661.7 [M+H]⁺.

Intermediate 198.1:(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To the solution of Intermediate 198.2 (1.30 g, 4.19 mmol) in THF (42 mL)was added subsequently (S)-butan-2-ol (0.466 g, 6.29 mmol),di-tert-butylazodicarboxylate (1.93 g, 8.39 mmol) and triphenylphosphine(polymer bound 3 mmol/g resin) (2.79 mg, 8.39 mmol) at 0° C. The mixturewas stirred for 75 min at RT. The reaction was filtered, washed withEtOAc and the filtrate concentrated. The residue was extracted betweenEtOAc (3×) and 1M aqueous NaHCO3 (1×). The organic phases were washedwith brine and dried over Na₂SO₄, filtered and evaporated to dryness.Purification of the residue by normal phase column chromatography,eluting with DCM-MeOH (98:2→95:5), gave the title compound aftercrystallization (TBME) as white crystals (628 mg, 1.728 mmol, 41%).HPLC: ^(D)t_(Ret)=1.06 min; LC-MS: m/z 360.1 [M+H]⁺;]⁺; ¹H NMR (400 MHz,DMSO-d₆): 0.82 (t, 3H), 1.13 (d, 3H), 1.46 (m, 1H), 1.52 (m, 1H),3.30-3.35 (d, 1H), 3.46-3.51 (d, 1H), 3.69 (s, 3H), 4.16 (m, 1H), 5.52(m, 1H), 6.76 (s, 1H), 6.80 (s, 1H), 7.32 (q, 4H), 8.48 (d, 1H).

Intermediate 198.2:(S)-1-(4-Chloro-phenyl)-7-hydroxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The mixture of Intermediate 75.6 (5.0 g, 14.46 mmol) andortho-phosphoric acid 85% (48.7 mL, 723 mmol) was stirred for 1.5 h at100° C. The reaction mixture was cooled to RT, poured (carefully) on 1Maqueous NaHCO₃ (500 mL), pH 7.0, and extracted with EtOAc (3×) Theorganic phases were washed with brine and dried over Na₂SO₄, filteredand evaporated to dryness. Purification of the residue by normal phasecolumn chromatography, eluting with DCM, gave the title compound asyellow foam (4.40 g, 14.20 mmol, 98%). HPLC: ^(D)t_(Ret)=0.78 min;LC-MS: m/z 304.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): 3.27-3.34 (d, 1H),3.44-3.49 (d, 1H), 3.71 (s, 3H), 5.46 (bs, 1H), 6.53 (s, 1H), 6.72 (s,1H), 7.32 (q, 4H), 8.41 (s, 1H), 8.85 (s, 1H).

Example 199(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{methyl-[4-(2-oxo-piperidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (29 mg, 0.045 mmol, 15%) was obtained as a yellowfoam from Intermediate 75.6 (100 mg, 0.289 mmol) and Intermediate 199.1(124 mg, 0.289), analogously to Example 130. HPLC: ^(D)t_(Ret)=1.23 min;LC-MS: m/z 645.6 [M+H]⁺.

Intermediate 199.1:1-(4-{[(5-Iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-piperidin-2-one

The title intermediate (412 mg, 0.964 mmol, 66%) was obtained as aslightly yellow foam from Intermediate 199.2 (680 mg, 1.466 mmol),analogously to Intermediate 197.1. HPLC: ^(J)t_(Ret)=4.34 min; LC-MS:m/z 428.2 [M+H]⁺.

Intermediate 199.2: 5-Chloro-pentanoic acid(4-{[(5-iodo-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-amide

The title intermediate (680 mg, 1.437 mmol, 99%) was obtained as aslightly yellow solid from Intermediate 130.4 (500 mg, 1.448 mmol) and5-chloro-pentanoyl chloride (225 mg, 1.448 mmol) analogously toIntermediate 195.2. HPLC: ^(J)t_(Ret)=4.45 min; LC-MS: m/z 464.4 [M+H]⁺.

Intermediate 200.1:4-[(S)-1-(4-Iodo-phenyl)-ethyl]-1-methyl-piperazin-2-one

The title intermediate (1.16 g, 3.38 mmol, 75%) was obtained as a whitesolid from Intermediate 200.2 (1.9 g, 3.99 mmol) analogously to Example79. HPLC: ^(K)t_(Ret)=4.71 min; LC-MS: m/z 345.2 [M+NH]⁺.

Intermediate 200.2:{[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-[(S)-1-(4-iodo-phenyl)-ethyl]-amino}-aceticacid methyl ester

The title intermediate (1.9 g, 3.99 mmol, 85%) was obtained as a whitesolid from Intermediate 200.3 (1.49 g, 4.67 mmol) analogously toIntermediate 79.2. HPLC: ^(K)t_(Ret)=6.37 min; LC-MS: m/z 477.4 [M+NH]⁺.

Intermediate 200.3: [(S)-1-(4-Iodo-phenyl)-ethylamino]-acetic acidmethyl ester

The title intermediate (1.5 g, 4.7 mmol, 74.4%) was obtained as a whitesolid from Intermediate 178.5 (1.56 g, 6.31 mmol) analogously toIntermediate 79.1. HPLC: ^(K)t_(Ret)=4.80 min; LC-MS: m/z 320.2 [M+NH]⁺.

Intermediate 201.1:4-((S)-1-{5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-2-yl}-ethyl)-3-oxo-piperazine-1-carboxylicacid tert-butyl ester

The title intermediate (106 mg, 0.16 mmol, 20.7%) was obtained as abeige solid from Intermediate 75.6 (286 mg, 0.82 mmol) and Intermediate201.2 (312 mg, 0.79 mmol) analogously to Example 75. HPLC:^(E)t_(Ret)=5.465 min; LC-MS: m/z 649.2 [M+H]⁺.

Intermediate 201.2:4-[(S)-1-(5-Bromo-pyridin-2-yl)-ethyl]-3-oxo-piperazine-1-carboxylicacid tert-butyl ester

The title intermediate (1.0 g, 2.6 mmol, 88%) was obtained as a whitesolid from Intermediate 201.3 (1.43 g, 2.96 mmol) analogously toIntermediate 178.2. HPLC: ^(E)t_(Ret)=5.029 min; LC-MS: m/z 386.0[M+H]⁺.

Intermediate 201.3:{2-[[(S)-1-(5-Bromo-pyridin-2-yl)-ethyl]-(2-chloro-acetyl)-amino]-ethyl}-carbamicacid tert-butyl ester

The title intermediate (1.43 g, 3.4 mmol, 72.2%) was obtained fromIntermediate 201.4 (1.62 g, 4.71 mmol) and chloroacetyl chloride (0.4mL, 4.99 mmol) analogously to Intermediate 178.3. HPLC:^(E)t_(Ret)=5.025 min; LC-MS: m/z 422.1 [M+H]⁺.

Intermediate 201.4:{2-[(S)-1-(5-Bromo-pyridin-2-yl)-ethylamino]-ethyl}-carbamic acidtert-butyl ester

The title intermediate (1.69 g, 4.91 mmol, 68.1%) was obtained as ayellow solid from Intermediate 201.5 (1.45 g, 7.21 mmol) and(2-Bromo-ethyl)-carbamic acid tert-butyl ester (2.1 g, 9.38 mmol)analogously to Intermediate 178.4. HPLC: ^(E)t_(Ret)=4.171 min; LC-MS:m/z 346.0 [M+H]⁺.

Intermediate 201.5: (S)-1-(5-Bromo-pyridin-2-yl)-ethylamine

Intermediate 201.6 (345 mg, 1.13 mmol) was dissolved in MeOH (5 mL).Then a solution of 4M HCl in dioxane (1.9 mL, 7.81 mmol) was added dropwise at 0° C. for 5 min. The reaction mixture was warmed up at RT. After1 h stirring, solvent was evaporated to give a white solid which waswashed with Et₂O and filtered under azote flow to give a white powder(293 mg, 1.05 mmol, 93%). HPLC: ^(E)t_(Ret)=3.025 min; LC-MS: m/z 202.9[M+H]⁺.

Intermediate 201.6: 2-Methyl-propane-2-sulfinic acid[(S)-1-(5-bromo-pyridin-2-yl)-ethyl]-amide

To a solution of Intermediate 201.7 (3.67 g, 12.68 mmol) in DCM (72 mL)was added drop wise 3M of Et₂O solution of methylmagnesium bromide (8.5mL, 25.4 mmol) at −60° C. The reaction mixture became intense orangecoloured, and then was warmed up to −50° C. for 30 min. Then thereaction mixture was warmed up slowly to 0° C. and the temperature wasmaintained at 0° C. with an ice bath for 3 h. The reaction mixture wasslowly poured into vigorously stirring cold saturated solution of NH₄Cl(100 mL). The organic layer was separated and the aqueous layer wasextracted twice with DCM. The combined organic layers were dried overMgSO4, filtered and evaporated to give a beige powder. The crudematerial was pre-absorbed onto SiO₂ and submitted to SiO₂ columnchromatography (elution with a gradient AcOEt/hexane from 40:60 to100:0). First eluting was collected and evaporated gave the titleintermediate (2.88 g, 9.25 mol, 72.9%). HPLC: ^(E)t_(Ret)=4.654 min;LC-MS: m/z 307.0 [M+H]⁺.

Intermediate 201.7: 2-Methyl-propane-2-sulfinic acid1-(5-bromo-pyridin-2-yl)-meth-(E)-ylideneamide

To a solution of 5-bromo-2-formyl-pyridine (3.0 g, 16.1 mmol) in dry THF(95 mL), (S)-tert-butylsulfinamide (2.05 g, 16.9 mmol) was added at RTunder argon. Then titanium tetra-isopropoxyide (7 mL, 33.9 mmol) wasadded drop wise. The reaction mixture was stirred at 73° C. (externaltemperature) for 2.5 h, and was allowed to cool down. The reactionmixture was slowly poured into a vigorously stirring mixture of ca. 200mL of brine and ice. The slurry was filtered and washed with DCM. Theorganic layer was separated and the aqueous layer was extracted twicewith DCM. The combined organic layers were washed with brine, dried overMgSO4, filtered, evaporated to give a brown solid. The product wastriturated in cold ether and successive filtered solids were combined togive the title intermediate (3.66 g, 12.4 mmol, 77%). HPLC:^(E)t_(Ret)=4.987 min; LC-MS: m/z 291.0 [M+H]⁺.

Example 202(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-{4-[(S)-1-(2-oxo-tetrahydro-pyrimidin-1-yl)-ethyl]-phenyl}-1,4-dihydro-2H-isoquinolin-3-one

The title compound (22 mg, 0.04 mmol, 13%) was obtained as a pale yellowsolid from Intermediate 202.1 (86 mg, 0.304 mmol) and Intermediate 75.6(100 mg, 0.289 mmol) analogously to Example 75. HPLC^(F)t_(Ret)=1.178;LC-MS: m/z 565.4 [M+NH₄]⁺.

Intermediate 202.1:1-[(S)-1-(4-Bromo-phenyl)-ethyl]-tetrahydro-pyrimidin-2-one

To a solution of S-(−)-1-(4-bromophenyl)ethylamine (1.06 g, 5.3 mmol) inTHF (10 mL) was added drop wise at RT 3-chloropropylisocyanate (0.546mL, 5.3 mmol). After 1 h, NaH (60% in mineral oil, 0.223 g, 5.57 mmol)was added and the resulting suspension was stirred at RT for 15 h. Thereaction was quenched with H₂O and NaHCO₃ and THF was removed byevaporation. The residue was partioned between DCM and H₂O. Afterseparation, the aqueous phase was re-extracted three times with DCM, thecombined organic extracts were washed with H₂O, saturated brine, driedover Na₂SO₄, filtered and evaporated to dryness. The resulting crudematerial was purified by Combi-Flash Companion™ (Isco Inc.) columnchromatography (SiO₂; gradient elution, DCM/[DCM/EtOH 9:1] 1:0→3:7)) toyield the title intermediate (1.39 g, 4.92 mmol, 93%) as colorlesscrystals. HPLC: ^(F)t_(Ret)=0.992; LC-MS: m/z 283.2 [M+H]⁺.

Example 203(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-O-1,4-dihydro-2H-isoquinolin-3-one

The title compound (100 mg, 0.150 mmol, 41%) was obtained as slightlyyellow crystals from Intermediate 198.1 (135 mg, 0.367 mmol) andIntermediate 132.1 (159 mg, 0.367 mmol) analogously to Example 130.HPLC: ^(D)t_(Ret)=1.15 min; LC-MS: m/z 660.6 [M+H]⁺.

Example 204(S)-1-(4-Chloro-phenyl)-7-cyclobutoxy-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (184 mg, 0.277 mmol, 52%) was obtained as beigecrystals from Intermediate 204.1 (190 mg, 0.526 mmol) and Intermediate132.1 (227 mg, 0.526 mmol) analogously to Example 130. HPLC:^(D)t_(Ret)=1.11 min; LC-MS: m/z 658.6 [M+H]⁺.

Intermediate 204.1:(S)-1-(4-Chloro-phenyl)-7-cyclobutoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (555 mg, 1.536 mmol, 32%) was obtained as whitecrystals from Intermediate 198.2 (1.50 g, 4.84 mmol) and cyclobutanol(0.529 g, 0.726 mmol) analogously to Intermediate 198.1. HPLC:^(D)t_(Ret)=1.05 min; LC-MS: m/z 358.3 [M+H]⁺.

Example 205(S)-1-(4-Chloro-phenyl)-6-methoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-7-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-1,4-dihydro-2H-isoquinolin-3-one

The title compound (110 mg, 0.158 mmol, 41%) was obtained as yellowcrystals from Intermediate 205.1 (150 mg, 0.383 mmol) and Intermediate132.1 (166 mg, 0.383 mmol) analogously to Example 130. HPLC:^(D)t_(Ret)=1.01 min; LC-MS: m/z 688.7 [M+H]⁺.

Intermediate 205.1:(S)-1-(4-Chloro-phenyl)-6-methoxy-7-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (132 mg, 0.340 mmol, 34%) was obtained as whitecrystals from Intermediate 198.2 (310 mg, 1.00 mmol) and(S)-(tetrahydrofuran-2-yl)-methanol (155 mg, 1.50 mmol), analogously toIntermediate 198.1. HPLC: ^(D)t_(Ret)=0.96 min; LC-MS: m/z 388.3 [M+H]⁺.

Example 2061-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

A suspension of Intermediate 166.2 (150 mg, 0.274 mmol), 2-pyrrolidinone(25.9 mg, 0.30 mmol), Cu(I)I (2.61 mg, 0.014 mmol), glycine (4.11 mg,0.055 mmol) and tripotasium phosphate (145 mg, 0.685 mmol) in THF (1.5mL) was heated at 70° C. for 17 h. The reaction mixture was diluted withEtOAc, washed with saturated aqueous solution of NaHCO₃ and brine. Thecombined organic layers were dried over Na₂SO₄, filtered and evaporatedto dryness. The resulting crude material was purified by Combi-FlashCompanion™ (Isco Inc.) column chromatography (SiO₂; gradient elutionAcOEt/DCM=7:3) to yield the title compound (26 mg, 0.051 mmol, 18.8%).HPLC: ^(K)t_(Ret)=6.81 min; LC-MS: m/z 505.4 [M+H]⁺.

Example 207(S)-1-(4-Chloro-phenyl)-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-7-[(R)-1-(tetrahydro-furan-2-yl)methoxy]-1,4-dihydro-2H-isoquinolin-3-one

The title compound (48 mg, 0.07 mmol, 9.0%) was obtained as slightlyyellow foam from Intermediate 205.1 (300 mg, 0.77 mmol) and Intermediate149.1 (296 mg, 0.77 mmol) analogously to Example 130. HPLC:^(E)t_(Ret)=4.686 min; LC-MS: m/z 689.7 [M+H]⁺.

Example 2081-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1,4-dihydro-2H-isoquinolin-3-one

The title compound (7.8 mg, 0.015 mmol, 2.5%) was obtained as a whitesolid from Intermediate 166.2 (340 mg, 0.621 mmol) andImidazolidin-2-one (107 mg, 1.24 mmol) by the reported method inSynthesis, 2008, 9, pp 1359-1366. HPLC: ^(E)t_(Ret)=5.090 min; LC-MS:m/z 506.0 [M+H]⁺.

Example 209(S)-1-(4-Chloro-phenyl)-7-cyclobutoxy-6-methoxy-2-(5-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyrazin-2-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (126 mg, 0.189 mmol, 38%) was obtained as a yellowfoam from Intermediate 204.1 (181 mg, 0.50 mmol) and Intermediate 149.1(193 mg, 0.50 mmol), analogously to Example 130. HPLC: ^(D)t_(Ret)=1.16min; LC-MS: m/z 659.6 [M+H]⁺.

Example 210(S)-7-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (176 mg, 0.258 mmol, 47%) was obtained as slightlyyellow crystals from Intermediate 198.1 (200 mg, 0.55 mmol) andIntermediate 130.1 (246 mg, 0.55 mmol), analogously to Example 130.HPLC: ^(D)t_(Ret)=1.05 min; LC-MS: m/z 674.6 [M+H]⁺.

Example 211(S)-1-(4-Chloro-phenyl)-7-cyclobutoxy-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (137 mg, 0.202 mmol, 48%) was obtained as slightlyyellow crystals from Intermediate 204.1 (150 mg, 0.415 mmol) andIntermediate 130.1 (187 mg, 0.415 mmol), analogously to Example 130.HPLC: ^(D)t_(Ret)=0.99 min; LC-MS: m/z 672.7 [M+H]⁺.

Example 212(S)-1-(4-Chloro-phenyl)-6-methoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-7-[(R)-1-(tetrahydro-furan-2-yl)methoxy]-1,4-dihydro-2H-isoquinolin-3-one

The title compound (17.1 mg, 0.024 mmol, 3.2%) was obtained as slightlyyellow foam from Intermediate 205.1 (300 mg, 0.77 mmol) and Intermediate130.1 (342 mg, 0.77 mmol) analogously to Example 130. HPLC:^(E)t_(Ret)=4.10 min; LC-MS: m/z 702.0 [M+H]⁺.

Intermediate 213.1:2-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-3-oxo-pentanenitrile

To a mixture of Intermediate 164.2 (138 mg, 0.30 mmol) andethylpropionate (0.14 mL, 1.2 mmol) in THF (0.8 mL) was added 1M THFsolution of LiHMDS at 0° C. (ice bath). The resulting mixture wasstirred at 0° C. for 30 min, a 0.25M HCl aqueous solution was added toquench the reaction and the mixture was extracted with AcOEt (2×). Thecombined organic fractions were dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude material was purified byCombi-Flash Companion™ (Isco Inc.) column chromatography (SiO₂; gradientelution AcOEt/DCM.) to yield the title intermediate (100 mg, 0.17 mmol,58% yield). HPLC: ^(G)t_(Ret)=7.619 min; LC-MS: m/z 517.4 [M+H]⁺.

Intermediate 214.1: 4-[(S)-1-(4-Iodo-phenyl)-ethyl]-morpholin-3-one

The title intermediate (239 mg, 0.70 mmol, 81%) was obtained as a whitesolid from Intermediate 214.2 (320 mg, 0.87 mmol) analogously toIntermediate 178.2. HPLC: ^(E)t_(Ret)=5.620 min; LC-MS: m/z 331.82[M+H]⁺.

Intermediate 214.2:2-(2-Chloro-ethoxy)-N-[(S)-1-(4-iodo-phenyl)-ethyl]-acetamide

To a solution of (2-chloro-ethoxy)-acetyl chloride (206 mg, 1.31 mmol)(which was made by the reported method in Heterocycles, vol 74, pp437-445) in THF (5 mL) was added Intermediate 178.5 (216 mg, 0.87 mmol)and Et₃N (0.48 mL, 3.5 mmol). After stirring for over night at RT, itwas quenched by addition of a saturated aqueous solution of NaHCO₃ andextracted with EtOAc. The organic phase was washed with a saturatedaqueous solution of NaHCO₃, dried (Na₂SO₄), filtered and concentrated.The residue was purified by column chromatography to yield (320 mg, 0.87mmol, 100%) of the title compound as a beige oil. HPLC:^(E)t_(Ret)=5.088 min; LC-MS: m/z 367.8 [M+H]⁺.

Intermediate 216.1:4-(4-{[(5-Bromo-6-fluoro-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-1-methyl-piperazin-2-one

The title intermediate (701 mg, 1.70 mmol, 99%) was obtained as a whitesolid from Intermediate 216.2 (950 mg, 1.71 mmol) analogously to Example79. HPLC: ^(G)t_(Ret)=5.876 min; LC-MS: m/z 415.3 [M+H]⁺.

Intermediate 216.2:{(4-{[(5-Bromo-6-fluoro-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-amino}-aceticacid methyl ester

The title intermediate (956 mg, 1.75 mmol, 91%) was obtained as a whitesolid from Intermediate 216.3 (750 mg, 1.93 mmol) andMethyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (502 mg, 2.90 mmol)analogously to Intermediate 79.2. HPLC: ^(G)t_(Ret)=7.363 min; LC-MS:m/z 547.2 [M+H]⁺.

Intermediate 216.3:(4-{[(5-Bromo-6-fluoro-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexylamino)-aceticacid methyl ester

The title intermediate (2.99 g, 7.7 mmol, 84%) was obtained as a whitesolid from Intermediate 216.4 (3.55 g, 9.12 mmol) andmethyl-2-bromoacetate (0.88 mL, 9.58 mmol) analogously to Intermediate79.1. HPLC: ^(G)t_(Ret)=6.097 min; LC-MS: m/z 390.3 [M+H]⁺.

Intermediate 216.4:(Trans-4-amino-cyclohexylmethyl)-(5-bromo-6-fluoro-pyridin-2-yl)-methyl-amine

The title intermediate (3.59 g, 9.23 mmol, 83%) was obtained as a whitesolid from Intermediate 216.5 (4.62 mg, 11.1 mmol) analogously toIntermediate 77.3. HPLC: ^(G)t_(Ret)=5.835 min; LC-MS: m/z 316.3 [M+H]⁺.

Intermediate 216.5:(4-{[(5-Bromo-6-fluoro-pyridin-2-yl)-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

The title intermediate (3.82 g, 9.18 mmol, 56.8%) was obtained as awhite solid from Intermediate 216.6 (6.5 g, 16.1 mmol) and 37% watersolution of formaldehyde (122 mL, 1616 mmol) analogously to Intermediate77.1. HPLC: ^(G)t_(Ret)=8.299 min; LC-MS: m/z 416.3 [M+H]⁺.

Intermediate 216.6:{4-[(5-Bromo-6-fluoro-pyridin-2-ylamino)-methyl]-trans-cyclohexyl}-carbamicacid tert-butyl ester

The title intermediate (6.56 g, 16.3 mmol, 72.4%) was obtained as awhite solid from (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester(5.63 g, 24.7 mmol) and 5-bromo-6-fluoro-pyridin-2-ylamine (4.3 g, 22.5mmol) analogously to Intermediate 75.7. HPLC: ^(G)t_(Ret)=7.827 min;LC-MS: m/z 402.3 [M+H]⁺.

Intermediate 219.1:4-((R)-1-{5-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-pyridin-2-yl}-ethyl)-3-oxo-piperazine-1-carboxylicacid tert-butyl ester

The title intermediate (100 mg, 0.154 mmol, 8.2%) was obtained as awhite solid from Intermediate 75.6 (671 mg, 1.94 mmol) and Intermediate219.2 (724 mg, 1.88 mmol) analogously to Example 75. HPLC:^(E)t_(Ret)=5.473 min; LC-MS: m/z 649.2 [M+H]⁺.

Intermediate 219.2:4-[(R)-1-(5-Bromo-pyridin-2-yl)-ethyl]-3-oxo-piperazine-1-carboxylicacid tert-butyl ester

The title intermediate (764 mg, 1.97 mmol, 99%) was obtained as a brownsolid from Intermediate 219.3 (837 mg, 1.99 mmol) analogously toIntermediate 178.2. HPLC: ^(E)t_(Ret)=5.031 min; LC-MS: m/z 385.9[M+H]⁺.

Intermediate 219.3:{2-[[(R)-1-(5-Bromo-pyridin-2-yl)-ethyl]-(2-chloro-acetyl)-amino]-ethyl}-carbamicacid tert-butyl ester

The title intermediate (837 mg, 1.99 mmol, 80%) was obtained fromIntermediate 219.4 (858 mg, 2.49 mmol) and chloroacetyl chloride (0.21mL, 2.62 mmol) analogously to Intermediate 178.3. HPLC:^(E)t_(Ret)=3.024 min; LC-MS: m/z 421.9 [M+H]⁺.

Intermediate 219.4:{2-[(R)-1-(5-Bromo-pyridin-2-yl)-ethylamino]-ethyl}-carbamic acidtert-butyl ester

The title intermediate (868 mg, 2.52 mmol, 73.2%) was obtained as anorange solid from Intermediate 219.5 (693 mg, 3.45 mmol) and(2-Bromo-ethyl)-carbamic acid tert-butyl ester (1.0 g, 4.48 mmol)analogously to Intermediate 178.4. HPLC: ^(E)t_(Ret)=4.085 min; LC-MS:m/z 346.1 [M+H]⁺.

Intermediate 219.4: (R)-1-(5-Bromo-pyridin-2-yl)-ethylamine

The title intermediate (1.03 g, 3.72 mmol, 92%) was obtained as a whitesolid from Intermediate 219.5 (1.24 g, 4.06 mmol) analogously toIntermediate 201.5. HPLC: ^(E)t_(Ret)=3.024 min; LC-MS: m/z 202.9[M+H]⁺.

Intermediate 219.5: 2-Methyl-propane-2-sulfinic acid[(R)-1-(5-bromo-pyridin-2-yl)-ethyl]-amide

The title intermediate (1.24 g, 4.06 mmol, 54.6%) was obtained as awhite solid from Intermediate 219.6 (2.15 g, 7.43 mmol) analogously toIntermediate 201.6. HPLC: ^(E)t_(Ret)=4.624 min; LC-MS: m/z 306.83[M+H]⁺.

Intermediate 219.6: 2-Methyl-propane-2-sulfinic acid[(R)-1-(5-bromo-pyridin-2-yl)-ethyl]-amide

The title intermediate (2.15 g, 7.43 mmol, 46.1%) was obtained as awhite solid from 5-bromo-2-formyl-pyridine (3.0 g, 16.1 mmol) and(R)-tert-butylsulfinamide (2.05 g, 16.9 mmol) analogously toIntermediate 201.7. HPLC: ^(E)t_(Ret)=5.029 min; LC-MS: m/z 290.74[M+H]⁺.

Example 2231-(4-Chloro-phenyl)-6-hydroxy-7-isopropoxy-2-(6-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

To the stirred mixture of Example 132 (100 mg, 0.155 mmol) and DMF (2.0mL) was subsequently added sodium hydride (15.6 mg, 0.650 mmol). Afterstirring 15 min at RT, butane-1-thiol (0.055 mL, 0.511 mmol) was addeddrop wise at RT and the resulting reaction mixture immediately heated(oil bath; 160° C.) for 15 min. The resulting crude material waspurified by reverse phase prep-HPLC (Waters system) to yield the racemictitle compound as slightly yellow foam (42 mg, 0.066 mmol, 43%). HPLC:^(J)t_(Ret)=3.99 min; LC-MS: m/z 632.6 [M+H]⁺.

Example 2247-((R)-sec-Butoxy)-1-(4-chloro-phenyl)-6-hydroxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (45 mg, 0.067 mmol, 45%) was obtained as slightlyyellow foam from Example 210 (100 mg, 0.148 mmol), analogously toExample 223. HPLC: ^(J)t_(Ret)=4.11 min; LC-MS: m/z 660.7 [M+H]⁺.

Example 2251-(4-Chloro-phenyl)-6-hydroxy-7-isopropoxy-2-(6-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (33 mg, 0.051 mmol, 48%) was obtained as beige foamfrom Example 130 (70 mg, 0.105 mmol), analogously to Example 223. HPLC:^(D)t_(Ret)=0.93 min; LC-MS: m/z 646.6 [M+H]⁺.

Example 2261-(4-Chloro-phenyl)-7-isopropoxy-6-d₃-methyoxy-2-(6-methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (57 mg, 0.085 mmol, 7.4%) was obtained as a yellowfoam from Intermediate 226.1 (400 mg, 1.147 mmol) and Intermediate 130.1(507 mg, 1.147 mmol), analogously to Example 130. HPLC: ^(D)t_(Ret)=0.99min; LC-MS: m/z 663.6 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) 0.89-1.13 (m,4H) 1.17 (d, J=6.05 Hz, 3H) 1.22 (d, J=5.85 Hz, 3H) 1.56-1.64 (m, 1H)1.63-1.82 (m, 4H) 2.18-2.27 (m, 1H) 2.66 (t, J=5.35 Hz, 2H) 2.78 (s, 3H)2.95 (s, 3H) 3.04 (s, 2H) 3.18 (t, J=5.25 Hz, 2H) 3.26-3.33 (m, 2H)3.55-4.01 (m, 2H) 4.38-4.46 (m, 1H) 5.95 (s, 1H) 6.51 (d, J=8.88 Hz, 1H)6.83 (s, 1H) 6.95 (s, 1H) 7.20 (dd, J=9.08, 2.62 Hz, 1H) 7.35 (s, 4H)7.76 (d, J=2.42 Hz, 1H).

Intermediate 226.1:1-(4-Chloro-phenyl)-7-isopropoxy-6-d₃-methoxy-1,4-dihydro-2H-isoquinolin-3-one

To the solution of Intermediate 226.2 (1.50 g, 4.52 mmol) and DMF (4.0mL) was added potassium carbonate (1.25 g, 9.04 mmol) and Iodomethane-d3(1.41 mL, 22.6 mmol). The suspension was stirred for 2 h at 60° C. Thereaction mixture was extracted between EtOAc (3×) and 1M aqueous NaHCO₃(1×). The organic phases were washed with brine and dried over Na₂SO₄,filtered and evaporated to dryness. Purification of the residue bynormal phase column chromatography, eluting with EtOAc-hexane, gave thetitle compound after crystallization (DCM-hexane) as white crystals(1.10 g, 3.09 mmol, 68%): HPLC: ^(J)t_(Ret)=5.02 min; LC-MS: m/z 349.3[M+H]⁺.

Intermediate 226.2:1-(4-Chloro-phenyl)-6-hydroxy-7-isopropoxy-1,4-dihydro-2H-isoquinolin-3-one

The title intermediate (4.20 g, 12.15 mmol, 70%) was obtained as yellowfoam from Intermediate 138.1 (6.0 g, 17.35 mmol), analogously to Example223. HPLC: ^(J)t_(Ret)=4.72 min; LC-MS: m/z 332.3 [M+H]⁺.

Example 2271-4-Chloro-phenyl)-7-isopropoxy-6-d₃-methoxy-2-(6-{d₃-methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (180 mg, 0.267 mmol, 47%) was obtained as slightlyyellow crystals from Intermediate 226.1 (200 mg, 0.562 mmol) andIntermediate 227.1 (253 mg, 0.562 mmol), analogously to Example 130.HPLC: ^(D)t_(Ret)=0.99 min; LC-MS: m/z 666.6 [M+H]⁺; ¹H NMR (600 MHz,DMSO-d₆) 0.95 (q, J=11.50 Hz, 2H), 1.03-1.14 (m, 2H), 1.17 (d, J=6.05Hz, 3H), 1.22 (d, J=6.05 Hz, 3H), 1.54-1.62 (m, 1H), 1.63-1.83 (m, 4H),2.23 (t, J=11.40 Hz, 1H), 2.66 (t, J=5.15 Hz, 2H), 2.78 (s, 3H), 3.04(s, 2H), 3.18 (t, J=5.25 Hz, 2H), 3.20-3.29 (m, 2H), 3.60 (d, 1H), 3.96(d, J=19.98 Hz, 1H), 4.35-4.47 (m, J=5.99, 5.99, 5.99, 5.99, 5.99, 5.75Hz, 1H), 5.95 (s, 1H), 6.51 (d, J=9.08 Hz, 1H), 6.83 (s, 1H), 6.95 (s,1H), 7.20 (dd, J=9.08, 2.62 Hz, 1H), 7.35 (s, 4H), 7.76 (d, J=2.42 Hz,1H).

Intermediate 227.1:4-(4-{[(5-Iodo-pyridin-2-yl)-d₃-methyl-amino]-methyl}-trans-cyclohexyl)-1-methyl-piperazin-2-one

The title intermediate (4.51 g, 10.03 mmol, 85%) was obtained as beigecrystals from Intermediate 227.2 (7.55 g, 11.77 mmol), analogously toExample 130.1. HPLC: ^(D)t_(Ret)=0.77 min; LC-MS: m/z 446.3 [M+H]⁺.

Intermediate 227.2:[[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-(4-{[(5-iodo-pyridin-2-yl)-d₃-methyl-amino]-methyl}-trans-cyclohexyl)-amino]-aceticacid methyl ester

The title intermediate (7.65 g, 11.92 mmol, 96%) was obtained as acolorless oil from Intermediate 227.3 (5.80 g, 12.42 mmol), analogouslyto Example 130.2. HPLC: ^(D)t_(Ret)=1.12 min; LC-MS: m/z 578.1 [M+H]⁺.

Intermediate 227.3:(4-{[(5-Iodo-pyridin-2-yl)-d₃-methyl-amino]-methyl}-trans-cyclohexyl-amino)-aceticacid methyl ester

The title intermediate (5.90 g, 12.63 mmol, 90%) was obtained as a beigeoil from Intermediate 227.4 (6.10 g, 17.34 mmol), analogously to Example130.3. HPLC: ^(D)t_(Ret)=0.69 min; LC-MS: m/z 420.9 [M+H]⁺.

Intermediate 227.4:(Trans-4-amino-cyclohexylmethyl)-(5-iodo-pyridin-2-yl)-d₃-methyl-amine

The title intermediate (6.22 g, 17.68 mmol, 94%) was obtained as a beigecrystals from Intermediate 227.5 (8.50 g, 18.77 mmol), analogously toExample 130.4. HPLC: ^(D)t_(Ret)=0.66 min; LC-MS: m/z 349.0 [M+H]⁺.

Intermediate 227.5:(4-{[(5-Iodo-pyridin-2-yl)-d₃-methyl-amino]-methyl}-trans-cyclohexyl)-carbamicacid tert-butyl ester

The title intermediate (8.60 g, 18.99 mmol, 56%) was obtained as a beigecrystals from Intermediate 227.6 (8.40 g, 33.9 mmol), analogously toExample 130.5. HPLC: ^(D)t_(Ret)=1.41 min; LC-MS: m/z 449.3 [M+H]⁺.

Intermediate 227.6: (Trans-4-d₃-methylaminomethyl-cyclohexyl)-carbamicacid tert-butyl ester

The title intermediate (8.50 g, 34.3 mmol, 51%) was obtained as a beigecrystals from trans-(4-formyl-cyclohexyl)-carbamic acid tert-butyl (15.5g, 67.5 mmol) and HCl salt of CD₃NH₂ (5.05 g, 70.9 mmol) analogously toExample 130.6. MS: m/z 245.38 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆):0.85-1.16 (m, 4H), 1.33-1.54 (m, 2H), 1.35 (s, 9H), 1.75 (d, 4H), 2.58(d, 2H), 3.12 (m, 1H), 6.69 (d, 1H).

Example 228(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(6-{d3-methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-pyridin-3-yl)-1,4-dihydro-2H-isoquinolin-3-one

The title compound (244 mg, 0.364 mmol, 42%) was obtained as whitecrystals from Intermediate 75.6 (300 mg, 0.859 mmol) and Intermediate227.1 (386 mg, 0.859 mmol), analogously to Example 130. HPLC:^(D)t_(Ret)=1.00 min; LC-MS: m/z 663.6 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆)0.95 (q, J=11.64 Hz, 2H), 1.05-1.15 (m, 2H), 1.17 (d, J=6.05 Hz, 3H),1.22 (d, J=6.05 Hz, 3H), 1.54-1.63 (m, 1H), 1.63-1.81 (m, 4H), 2.23 (t,J=11.20 Hz, 1H), 2.66 (t, J=5.15 Hz, 2H), 2.78 (s, 3H), 3.04 (s, 2H),3.18 (t, J=5.25 Hz, 2H), 3.21-3.31 (m, 2H), 3.60 (d, 1H), 3.72 (s, 3H),3.96 (d, 1H), 4.35-4.47 (m, 1H), 5.95 (s, 1H), 6.51 (d, J=9.08 Hz, 1H),6.83 (s, 1H), 6.95 (s, 1H), 7.20 (dd, J=9.08, 2.42 Hz, 1H), 7.35 (s,4H), 7.76 (d, J=2.42 Hz, 1H).

In another embodiment of the invention there is provided a compound asexemplified herein.

Other related reference compounds are:

-   1-(2-Chloro-phenyl)-6,7-diethoxy-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one,-   6,7-Diethoxy-1-(2-fluoro-phenyl)-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one-   6,7-Diethoxy-2-(4-methoxy-phenyl)-1-o-tolyl-1,4-dihydro-2H-isoquinolin-3-one-   6,7-Diethoxy-2-(4-methoxy-phenyl)-1-(2-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one-   6,7-Diethoxy-1-(3-fluoro-phenyl)-2-(4-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one-   6,7-Diethoxy-2-(4-methoxy-phenyl)-1-m-tolyl-1,4-dihydro-2H-isoquinolin-3-one,    and-   6,7-Diethoxy-2-(4-methoxy-phenyl)-1-(3-methoxy-phenyl)-1,4-dihydro-2H-isoquinolin-3-one.

TABLE 2 Hdm2 and Hdm4 inhibitory activity of representative compounds ofthe present invention. IC₅₀ (μM) of p53-Hdm2 IC₅₀ (μM) of p53-Hdm4inhibition (TR-FRET) inhibition (TR-FRET) Example Assay Assay  1 0.115990.18  3 44.9235 nd  4 71.1878 nd  5 50.6536 nd  6 5.505 57.73  770.2577 nd  8 0.7232 nd  9 5.6602 nd 10 16.7589 nd 12 0.8843 60.64 131.6775 nd 14 0.3889 65.67 16 1.3095 nd 17 0.9706 45.89 18 0.6247 nd 2010.2885 nd 21 25.2904 nd 22 0.2458 51.15 23 1.3811 nd 24 0.4242 41.7 250.1346 nd 26 0.1153 62.61 28 0.0818 60.15 29 0.3316 38.39 30 0.158523.72 31 0.1538 11.38 32 0.1201 8.13 34 0.5927 nd 35 0.8769 nd 36 1.38382.03 38 0.1904 17.46 39 16.203 nd 41 0.4105 41.37 42 0.0084 19.32 430.6072 nd 44 1.4681 nd 45 0.0047 6.01 46 0.0091 10.4 47 0.0035 4.06 480.006 8.01 49 0.0107 nd 50 0.0123 24.51 51 0.0037 4.04 52 0.0058 4.54 530.0023 2.3 55 0.1898 63.71 56 0.0471 26.74 57 0.0724 32.78 59 0.051229.06 60 0.0472 30.11 61 0.0426 30.79 62 0.1142 77.38 63 0.2599 91.98 640.2026 64.38 65 0.0693 43.66 66 0.106 67.48 67 0.0152 16.72 68 0.02218.15 69 0.1119 41.62 70 0.0152 11.21 72 0.0269 17.86   73a 0.0019 2.88 73b 0.7875 52.51 75 0.0025 2.24 76 0.0027 2.89 77 0.0036 9.87 78 0.004922.75 79 0.0016 1.66 80 0.0029 2.8 81 0.0033 2.31 82 0.0063 7.05 830.0018 3.01 84 0.0014 1.84 87 0.0333 27.9 88 0.0349 24.89 89 0.0142 9 900.2167 nd 92 0.7191 nd 93 0.0215 12.5 94 0.0983 34.46 95 0.104 38.04103  0.002 1.70 105  0.0018 2.03 106  0.0008 2.10 113  0.0014 1.73 122 0.0077 8.34 123  0.0047 6.83 124  0.0057 nd 125  0.007 8.12 130  0.00171.63 134  0.0041 5.09 140  0.0043 3.75 148  0.0012 2.15 149  0.0043 4.13178  0.0071 8.58 192  0.521 n.d 204  0.0021 1.36 205  0.0038 1.56 218 0.033 36.5 nd = not determined.

In another embodiment of the invention there is provided a crystallineform I of the sulphate salt of the compound of Example 106,((S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one),and a process to make said crystalline form. The disclosed crystallinesulphate salt form I provides a significant improvement in processingproperties compared to the free base amorphous form, and providesimprovements in solubility and stability.

Process to Make the Crystalline Form I of the Sulphate Salt of theCompound of Example 106:

A: Slurry Method

Solvent: isopentyl alcohol

(1) About 5 mg of drug substance was first dissolved in 100 μl IPA.

(2) 364 μl 0.025N sulphuric acid was added to the solution very slowly,allowing slow precipitation during the stirring at 60° C.

(3) The suspension was stirred at room temperature overnight.

(4) The supernatant was removed by centrifugation.

(5) The solid product was dried under vacuum oven at 40° C. overnightand investigated by XRPD (X-ray powder diffraction). The process wasscaled up, and scale-up samples were further characterized using XRPD.Crystalline form I was obtained.

The X-ray diffraction data were collected at room temperature using aBruker AXS GMBH D8Discover powder X-ray diffractometer (Cu Kα radiation)fitted with an automatic sample changer, a theta-theta goniometer,automatic beam divergence slits, a secondary monochromator and ascintillation counter. Samples were prepared for analysis by gentlypressing the compound in one glass filter. The sample was rotated whilebeing irradiated with Copper Kα1 X-rays (wavelength=1.54184 Ångstroms)with the x-ray tube operated at 40 kV/40 mA. The analyses were performedwith the goniometer running in continuous mode set for a 120 secondcount per 0.02 degree step over a two theta range of 5 degree to 45degree. The peaks obtained were aligned against the silicon referencestandard.

Instrument Name: X-ray Diffractometer

Model: D8 Discover

Manufacturer: Bruker AXS GMBH

Wavelength: 1.54184 A (Cu)

Generator setting: 40.00 KV, 40.00 mA Monochromator

Detector: HI-STAR

Frame Size: 1024 pixels, 107.79 mm

Experiment Method:

2-Theta start: 5.0 degree

2-Theta end: 45.0 degree

Pixel overlap: 20%

Integration stepsize: 0.02 degree

Scan time: 120 seconds

Temperature: Room Temperature

TABLE A XRPD data of Example 106 sulphate salt crystalline form I (A:slurry method) Angle d value Intensity % 2-Theta ° Angstrom % 17.1 5.20126 18.7 4.74 103 20.4 4.35 89.2 21.4 4.14 93.5 22.9 3.89 183 23.5 3.78111 24.1 3.68 132 28.3 3.15 88.9B: Anti-Solvent Method

Solvents: isopropyl alcohol

(1) About 5 mg of drug substance was first dissolved in 91 μl 0.025Nsulfuric acid IPA.

(2) Anti-solvent methyl tert-butyl ether was added to precipitate thecompound during the stirring at 55-60° C.

(3) The suspension was stirred at 55-60° C. overnight.

(4) By centrifugation, the supernatant was removed.

(5) The solid product was dried in the vacuum oven at 40° C. overnightand investigated by XRPD. The process was scaled up. Scale-up sampleswere further characterized using XRPD. Crystalline form I was obtained.

TABLE B XRPD data of Example 106 sulphate salt crystalline form I (B:Anti-solvent method) Angle d value Intensity % 2-Theta ° Angstrom % 13.56.56 89.1 16.6 5.35 117 16.9 5.24 226 18.8 4.73 114 19.8 4.48 167 21.34.17 117 22.7 3.92 270 23.9 3.72 172 24.9 3.57 180 error +/−0.2°.

It will be appreciated by the skilled crystallographer that the relativeintensities of the various peaks reported in the Tables and Figures mayvary due to a number of factors such as the orientation effects of thecrystals in the X-ray beam, and the purity of the material beinganalysed. The peak positions may also shift for variations in sampleweight but will remain substantially the same.

The sulphate salt formed is believed to be the bisulphate salt.

An another embodiment of the invention there is provided a crystallineform I of(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-onesulphate salt having a powder X ray diffraction pattern using Cu Kαradiation which includes the following peaks:

Angle 2-Theta °: 18.8, 21.3 and 22.7, error +/−0.2°.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 discloses the X-ray powder diffraction data for Example 106sulphate salt crystalline form I, as obtained using the slurry method.

FIG. 2 discloses the X-ray powder diffraction data for Example 106sulphate salt crystalline form I, as obtained using the anti-solventmethod.

FURTHER EMBODIMENTS

1. A substituted nitrogen containing bicyclic heterocycle of the formula(I) and/or tautomers and/or N-oxides and/or pharmaceutically acceptablesalts thereof,

wherein

Z is CH₂ or N—R⁴;

X is halogen;

R⁴ is selected from the group consisting of

H—

C₁-C₇-alkyl-;

R⁶ is independently selected from the group consisting of

H—

R′O—

(R′)₂N—;

R⁷ is independently selected from the group consisting of

R′O—

(R′)₂N—;

R′ is selected from the group consisting of

H—

C₁-C₇-alkenyl-

halo-C₁-C₇-alkyl-

halo-C₁-C₇-alkenyl-

C₃-C₁₂-cycloalkyl-

heterocyclyl-

aryl-

hydroxy-C₁-C₇-alkyl-

C₁-C₇-alkoxy-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-

C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-

heterocyclyl-C₁-C₇-alkyl-

aryl-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-

halo-C₁-C₇-alkyl-carbonyl-

hydroxy-C₁-C₇-alkyl-carbonyl-

C₁-C₇-alkoxy-C₁-C₇-alkyl-carbonyl-

amino-C₁-C₇-alkyl-carbonyl-

N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-

N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-

C₃-C₁₂-cycloalkyl-carbonyl-

heterocyclyl-C₁-C₇-alkyl-carbonyl-

aryl-C₁-C₇-alkyl-carbonyl-

C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-carbonyl-

heterocyclyl-carbonyl-

aryl-carbonyl-

C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

halo-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

hydroxy-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkoxy-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-

N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-

alkyl-

C₃-C₁₂-cycloalkyl-carbonyl-C₁-C₇-alkyl-

heterocyclyl-carbonyl-C₁-C₇-alkyl-

aryl-carbonyl-C₁-C₇-alkyl-

carbonyl-C₁-C₇-alkyl-

hydroxy-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl-

amino-carbonyl-C₁-C₇-alkyl-

N—C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-

N,N-di-C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-

C₃-C₁₂-cycloalkyl-carbonyl-C₁-C₇-alkyl-

heterocyclyl-carbonyl-C₁-C₇-alkyl-

aryl-carbonyl-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

halo-C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-

halo-C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-

-   -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are        unsubstituted or substituted by 1-4 substituents selected from        C₁-C₇-alkyl, halo-C₁-C₇-alkyl, halogen, hydroxy, C₁-C₇-alkoxy,        amino, nitro or cyano;

R¹ is selected from the group consisting of

halogen-

cyano-

nitro-

C₁-C₇-alkenyl-

halo-C₁-C₇-alkyl-

hydroxy-

C₁-C₇-alkoxy-

amino-

N—C₁-C₇-alkyl-amino-

N,N-di-C₁-C₇-alkyl-amino-

hydroxy-C₁-C₇-alkyl-

amino-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-

C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-;

n is 0 to 2;

R² is selected from

-   -   (A) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   C₁-C₇-alkyl-        -   halo-C₁-C₇-alkyl-        -   hydroxy-        -   C₁-C₇-alkoxy-        -   hydroxy-C₁-C₇-alkyl-;            or

    -   (B) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by a substituent selected from        -   cyano-        -   halogen-        -   nitro-        -   halo-C₁-C₇-alkyl-        -   hydroxy-C₁-C₇-alkyl-        -   hydroxy-carbonyl-        -   C₁-C₇-alkoxy-carbonyl-        -   C₁-C₇-alkyl-carbonyl-        -   C₁-C₇-alkoxy-        -   (C-bound)-heterocyclyl-            -   wherein (C-bound)-heterocyclyl is unsubstituted or                substituted by 1-4 substituents selected from                C₁-C₇-alkyl, halo-C₁-C₇-alkyl, halogen, hydroxy,                C₁-C₇-alkoxy, amino, nitro or cyano;            -   and optionally substituted by 1-2 additional                substituents selected from            -   halogen-            -   cyano-            -   halo-C₁-C₇-alkyl-            -   hydroxy-            -   C₁-C₇-alkoxy-            -   hydroxy-C₁-C₇-alkyl-;                or

    -   (C) phenyl,        -   substituted in ortho-position by            R³O—        -   and substituted in para- or meta-position by a substituent            selected from methyl or chloro;            or

    -   (D) (C-bound)-heterocycle selected from

-   -   -   wherein Z is a 4-6 membered heterocyclic ring, annulated to            phenyl in para and meta position, containing 1-3 heteroatoms            selected from N, O or S,

    -   which is optionally substituted by 1-2 additional substituents        selected from

    -   halogen-

    -   cyano-

    -   halo-C₁-C₇-alkyl-

    -   hydroxy-

    -   C₁-C₇-alkoxy-

    -   hydroxy-C₁-C₇-alkyl-;        -   wherein R³ is independently selected from        -   H—        -   C₁-C₇-alkyl-        -   C₃-C₁₂-cycloalkyl-        -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-        -   (R⁵)₂N—C₁-C₇-alkyl-        -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-        -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-carbonyl-        -   R⁵O—C₃-C₁₂-cycloalkyl-        -   R⁵O—C₁-C₇-alkyl-        -   R⁵O—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-        -   R⁵O—C₃-C₁₂-cycloalkyl-carbonyl-        -   (R⁵)₂N-carbonyl-C₁-C₇-alkyl-        -   R⁵O-carbonyl-C₁-C₇-alkyl-        -   aryl-C₁-C₇-alkyl-        -   heterocyclyl-C₁-C₇-alkyl-        -   C₁-C₇-alkyl-carbonyl-        -   heterocyclyl-carbonyl-        -   aryl-carbonyl-        -   C₃-C₁₂-cycloalkyl-carbonyl-        -   C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-        -   heterocyclyl-        -   aryl-            -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are                unsubstituted or substituted by 1-4 substituents                selected from            -   halogen-            -   C₁-C₇-alkyl-            -   halo-C₁-C₇-alkyl-            -   C₁-C₇-alkyl-carbonyl-            -   C₃-C₁₂-cycloalkyl-carbonyl-            -   C₁-C₇-alkyl-sulfonyl-            -   amino-sulfonyl-            -   N—C₁-C₇-alkyl-amino-sulfonyl-            -   N,N-di-C₁-C₇-alkyl-amino-sulfonyl-            -   amino-carbonyl-            -   N—C₁-C₇-alkyl-amino-carbonyl-            -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-            -   oxo=        -   or        -   two R³, together with the N to which they are attached my            form a 3-9 membered heterocyclic ring, optionally containing            1-4 additional heteroatoms selected from N, O or S, said            heterocyclic ring is unsubstituted or substituted by 1-3            substituents selected from:        -   halogen-        -   C₁-C₇-alkyl-        -   halo-C₁-C₇-alkyl-        -   oxo=        -   hydroxy-        -   C₁-C₇-alkoxy-        -   amino-        -   N—C₁-C₇-alkyl-amino-        -   N,N-di-C₁-C₇-alkyl-amino-        -   hydroxy-carbonyl-        -   C₁-C₇-alkoxy-carbonyl-        -   amino-carbonyl-        -   N—C₁-C₇-alkyl-amino-carbonyl-        -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-        -   C₁-C₇-alkyl-carbonyl-        -   C₁-C₇-alkyl-carbonyl-amino-        -   C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-;        -   and        -   R⁵ is independently selected from:        -   H—        -   C₁-C₇-alkyl-        -   C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl-        -   amino-carbonyl-C₁-C₇-alkyl-        -   N—C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-        -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-        -   C₁-C₇-alkyl-sulfonyl-        -   amino-sulfonyl-        -   N—C₁-C₇-alkyl-amino-sulfonyl-        -   N,N-di-C₁-C₇-alkyl-amino-sulfonyl-        -   amino-carbonyl-        -   N—C₁-C₇-alkyl-amino-carbonyl-        -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-        -   C₃-C₁₂-cycloalkyl-carbonyl-        -   C₁-C₇-alkoxy-carbonyl-amino-C₁-C₇-alkyl-        -   C₁-C₇-alkoxy-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-        -   C₁-C₇-alkoxy-carbonyl-        -   or        -   two R⁵, together with the N to which they are attached my            form a 3-9 membered heterocyclic ring, optionally containing            1-4 additional heteroatoms selected from N, O or S, said            heterocyclic ring is unsubstituted or substituted by 1-3            substituent selected from C₁-C₇-alkyl-        -   oxo=;

    -   with the proviso that if Z is CH₂, n is 0 and R² is selected        from

    -   para-C₁-C₃-alkyl-phenyl-

    -   para-(halo-C₁-C₃-alkyl)-phenyl-

    -   para-C₁-C₃-alkoxy-phenyl-

    -   para-halo-phenyl-

    -   para-nitro-phenyl-

    -   para-(C₁-C₃-alkoxy-carbonyl)-phenyl-

    -   para-(hydroxy-carbonyl)-phenyl-

    -   wherein the phenyl is optionally substituted by 1-2 additional        substituents, then R⁶ and R⁷ are not both ethoxy or methoxy.        2. A compound according to embodiment 1, wherein

R² is selected from

-   -   phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   halo-C₁-C₇-alkyl-        -   hydroxy-        -   C₁-C₇-alkoxy-        -   hydroxy-C₁-C₇-alkyl.            3. A compound according to embodiment 2, wherein Z is CH₂.            4. A compound according to anyone of embodiments 2 to 3,            wherein

R⁶ is selected from

R′O—

and

R⁷ is selected from

R′O—;

or

R⁶ is selected from

H—

and

R⁷ is selected from

(R′)₂N—.

5. A compound according to anyone of embodiments 2 to 4, wherein

R′ is selected from the group consisting of

H—

C₁-C₄-alkyl-

C₁-C₄-alkenyl-

halo-C₁-C₄-alkyl-

C₃-C₁₂-cycloalkyl-

C₃-C₁₂-cycloalkyl-C₁-C₂-alkyl-

-   -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are        unsubstituted or substituted by 1-2 substituents selected from        C₁-C₄-alkyl, halo-C₁-C₄-alkyl, halogen, hydroxy, C₁-C₄-alkoxy,        amino, nitro or cyano.        6. A compound according to anyone of embodiments 2 to 5, wherein        n is 0.        7. A compound according to any one of embodiments 2 to 6,        wherein    -   R³ is independently selected from    -   H—    -   C₁-C₇-alkyl-    -   C₃-C₁₂-cycloalkyl-    -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-    -   (R⁵)₂N—C₁-C₇-alkyl-    -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   (R⁵)₂N—C₃-C₁₂-cycloalkyl-carbonyl-    -   R⁵O—C₁-C₇-alkyl-    -   (R⁵)₂N-carbonyl-C₁-C₇-alkyl-    -   R⁵O-carbonyl-C₁-C₇-alkyl-    -   aryl-C₁-C₇-alkyl-    -   heterocyclyl-C₁-C₇-alkyl-    -   C₁-C₇-alkyl-carbonyl-    -   heterocyclyl-carbonyl-    -   C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-    -   heterocyclyl-    -   wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are        unsubstituted or substituted by 1-4 substituents selected from        -   halo-        -   halo-C₁-C₇-alkyl-        -   C₁-C₇-alkyl-carbonyl-        -   C₃-C₁₂-cycloalkyl-carbonyl-        -   C₁-C₇-alkyl-sulfonyl-        -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-        -   oxo=    -   or    -   two R³, together with the N to which they are attached my form a        3-9 membered heterocyclic ring, optionally containing 1-4        additional heteroatoms selected from N, O or S, said        heterocyclic ring is unsubstituted or substituted by 1-3        substituents selected from:    -   C₁-C₇-alkyl-    -   oxo=    -   hydroxy-    -   amino-    -   N,N-di-C₁-C₇-alkyl-amino-    -   hydroxy-carbonyl-    -   C₁-C₇-alkoxy-carbonyl-    -   amino-carbonyl-    -   N—C₁-C₇-alkyl-amino-carbonyl-    -   C₁-C₇-alkyl-carbonyl-    -   C₁-C₇-alkyl-carbonyl-amino-;        and    -   R⁵ is independently selected from:    -   H—    -   C₁-C₇-alkyl-    -   C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl-    -   amino-carbonyl-C₁-C₇-alkyl-    -   C₁-C₇-alkyl-sulfonyl-    -   N,N-di-C₁-C₇-alkyl-amino-carbonyl-    -   C₁-C₇-alkoxy-carbonyl-amino-C₁-C₇-alkyl-    -   C₁-C₇-alkoxy-carbonyl-    -   or    -   two R⁵, together with the N to which they are attached my form a        3-9 membered heterocyclic ring, optionally containing 1-4        additional heteroatoms selected from N, O or S, said        heterocyclic ring is unsubstituted or substituted by 1-3        substituent selected from C₁-C₇-alkyl-    -   oxo=.        8. A compound according to any one of embodiments 2 to 7,        wherein    -   R³ is independently selected from    -   H—    -   C₁-C₄-alkyl-    -   C₃-C₁₂-cycloalkyl-    -   (R⁵)₂N—C₃-C₇-cycloalkyl-    -   (R⁵)₂N—C₁-C₇-alkyl-    -   (R⁵)₂N—C₃-C₇-cycloalkyl-C₁-C₂-alkyl-    -   (R⁵)₂N—C₃-C₇-cycloalkyl-carbonyl-    -   aryl-C₁-C₂-alkyl-    -   heterocyclyl-C₁-C₂-alkyl-    -   C₁-C₄-alkyl-carbonyl-    -   heterocyclyl-carbonyl-    -   C₃-C₇-cycloalkyl-C₁-C₂-alkyl-    -   heterocyclyl-        wherein aryl, heterocyclyl and C₃-C₁₂-cycloalkyl are        unsubstituted or substituted by 1-2    -   substituents selected from        -   halo-        -   C₁-C₄-alkyl-        -   C₁-C₄-alkyl-carbonyl-        -   C₃-C₇-cycloalkyl-carbonyl-        -   C₁-C₄-alkyl-sulfonyl-        -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-        -   oxo=    -   or    -   two R³, together with the N to which they are attached my form a        4-7 membered heterocyclic ring, optionally containing 1-2        additional heteroatoms selected from N, O or S, said        heterocyclic ring is unsubstituted or substituted by 1-2        substituents selected from:    -   C₁-C₄-alkyl-    -   oxo=    -   hydroxy-    -   amino-    -   N,N-di-C₁-C₄-alkyl-amino-    -   hydroxy-carbonyl-    -   C₁-C₄-alkoxy-carbonyl-    -   amino-carbonyl-    -   N—C₁-C₄-alkyl-amino-carbonyl-    -   C₁-C₄-alkyl-carbonyl-    -   C₁-C₄-alkyl-carbonyl-amino-;    -   and    -   R⁵ is independently selected from:    -   H—    -   C₁-C₄-alkyl-    -   C₁-C₄-alkoxy-carbonyl-C₁-C₂-alkyl-    -   amino-carbonyl-C₁-C₂-alkyl-    -   C₁-C₄-alkyl-sulfonyl-    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-    -   C₁-C₄-alkoxy-carbonyl-amino-C₁-C₂-alkyl-    -   C₁-C₄-alkoxy-carbonyl-        or    -   two R⁵, together with the N to which they are attached my form a        4-7 membered heterocyclic ring, optionally containing 1-4        additional heteroatoms selected from N, O or S, said        heterocyclic ring is unsubstituted or substituted by 1-2        substituent selected from:    -   C₁-C₄-alkyl-    -   oxo=.        9. A compound of formula (I) or pharmaceutically acceptable salt        and/or solvate thereof,

wherein

Z is CH₂ or N—R⁴;

X is halogen;

R⁴ is selected from the group consisting of

H—

C₁-C₄-alkyl-;

R⁶ is independently selected from the group consisting of

H—

R′O—

(R′)₂N—;

R⁷ is independently selected from the group consisting of

R′O—

(R′)₂N—;

each R′ is independently selected from the group consisting of

H—

C₁-C₆-alkyl-

C₁-C₆-alkenyl-

halo-C₁-C₄-alkyl-

halo-C₁-C₄-alkenyl-

C₃-C₇-cycloalkyl-

heterocyclyl-

aryl-

hydroxy-C₁-C₄-alkyl-

C₁-C₄-alkoxy-C₁-C₄-alkyl-

amino-C₁-C₄-alkyl-

N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

C₃-C₇-cycloalkyl-C₁-C₄-alkyl-

heterocyclyl-C₁-C₄-alkyl-

aryl-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-

halo-C₁-C₄-alkyl-carbonyl-

hydroxy-C₁-C₄-alkyl-carbonyl-

C₁-C₄-alkoxy-C₁-C₄-alkyl-carbonyl-

amino-C₁-C₄-alkyl-carbonyl-

N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl-

N,N-di-C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl-

C₃-C₇-cycloalkyl-carbonyl-

heterocyclyl-C₁-C₄-alkyl-carbonyl-

aryl-C₁-C₄-alkyl-carbonyl-

C₃-C₇-cycloalkyl-C₁-C₄-alkyl-carbonyl-

heterocyclyl-carbonyl-

aryl-carbonyl-

C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

halo-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

hydroxy-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

C₁-C₄-alkoxy-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

amino-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-

C₃-C₇-cycloalkyl-carbonyl-C₁-C₄-alkyl-

heterocyclyl-carbonyl-C₁-C₄-alkyl-

aryl-carbonyl-C₁-C₄-alkyl-

carbonyl-C₁-C₄-alkyl-

hydroxy-carbonyl-C₁-C₄-alkyl-

C₁-C₄-alkoxy-carbonyl-C₁-C₄-alkyl-

amino-carbonyl-C₁-C₄-alkyl-

N—C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-

C₃-C₇-cycloalkyl-carbonyl-C₁-C₄-alkyl-

heterocyclyl-carbonyl-C₁-C₄-alkyl-

aryl-carbonyl-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-amino-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

halo-C₁-C₄-alkyl-carbonyl-amino-C₁-C₄-alkyl-

halo-C₁-C₄-alkyl-carbonyl-N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

-   -   wherein aryl, heterocyclyl and C₃-C₇-cycloalkyl are        unsubstituted or substituted by 1-4 substituents selected from        C₁-C₄-alkyl, halo-C₁-C₄-alkyl, halogen, hydroxy, C₁-C₄-alkoxy,        amino, nitro or cyano;

each R¹ is independently selected from the group consisting of

halogen-

cyano-

nitro-

C₁-C₄-alkyl-

C₁-C₄-alkenyl-

halo-C₁-C₄-alkyl-

hydroxy-

C₁-C₄-alkoxy-

amino-

N—C₁-C₄-alkyl-amino-

N,N-di-C₁-C₄-alkyl-amino-

amino-carbonyl-amino-

N—C₁-C₄-alkyl-amino-carbonyl-amino-

N,N-di-C₁-C₄-alkyl-amino-carbonyl-amino-

C₁-C₄ alkyl-carbonyl-amino-

amino-carbonyl-

N—C₁-C₄-alkyl-amino-carbonyl-

N,N-di-C₁-C₄-alkyl-amino-carbonyl-

hydroxy-C₁-C₄-alkyl-

amino-C₁-C₄-alkyl-

N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

N,N-di-C₁-C₄-alkyl-amino-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-amino-C₁-C₄-alkyl-

C₁-C₄-alkyl-carbonyl-N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-;

n is 0, 1 or 2;

R² is selected from

-   -   (A) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by            (R³)₂N—Y—            -   wherein Y is absent (a bond) or            -   (R³)₂N—Y— is selected from

-   -   -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   C₁-C₄-alkyl-        -   hydroxy-        -   C₁-C₄-alkoxy-        -   hydroxy-C₁-C₄alkyl-;            or

    -   (B) phenyl, 2-pyridyl or 3-pyridyl        -   substituted in para-position by a substituent selected from        -   cyano-        -   halogen-        -   nitro-        -   C₁-C₄-alkyl-        -   hydroxy-C₁-C₄-alkyl-        -   hydroxy-carbonyl-        -   C₁-C₄-alkoxy-carbonyl-        -   C₁-C₄-alkyl-carbonyl-        -   C₁-C₄-alkoxy-        -   (C-bound)-heterocyclyl-            -   wherein (C-bound)-heterocyclyl is unsubstituted or                substituted by 1-4 substituents selected from                C₁-C₄-alkyl, halo-C₁-C₄-alkyl, halogen, hydroxy,                C₁-C₄-alkoxy, amino, nitro or cyano;        -   and optionally substituted by 1-2 additional substituents            selected from        -   halogen-        -   cyano-        -   C₁-C₄-alkyl-        -   hydroxy-        -   C₁-C₄-alkoxy-        -   (C-bound or N-bound)heterocyclyl-C₁-C₄-alkyl-        -   hydroxy-C₁-C₄-alkyl-;            or

    -   (C) phenyl,        -   substituted in ortho-position by        -   R³O—            -   and substituted in para- or meta-position by a                substituent selected from methyl, chloro,                C₁-C₄-alkyl-carbonyl- or C₁-C₄-alkoxy-carbonyl-;

    -   (D) (C-bound)-heterocycle selected from

-   -   -   -   wherein Z is a 4-6 membered heterocyclic ring, annulated                to phenyl in para and meta position, containing 1-3                heteroatoms selected from N, O or S,

        -   which is optionally substituted by 1-2 additional            substituents selected from

        -   halogen-

        -   cyano-

        -   C₁-C₄-alkyl-

        -   halo-C₁-C₄-alkyl-

        -   hydroxy-

        -   C₁-C₄-alkoxy-

        -   hydroxy-C₁-C₄-alkyl-;

    -   (E) pyrazin-2-yl (relative to the isoquinolinone or        quinazolinone),        substituted at the 5 position by:

-   -   (F) pyridazin-3-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 6 position by:

or

-   -   (G) pyrimidin-2-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 5 position by:

wherein each R³ is independently selected from

-   -   H—    -   C₁-C₄-alkyl-    -   hydroxy-C₁-C₄-alkyl-    -   C₃-C₇-cycloalkyl-    -   C₁-C₄-alkoxy-C₁-C₄-alkyl-carbonyl-    -   amino-C₁-C₄-alkyl-carbonyl    -   N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl    -   N,N-di C₁-C₄-alkyl-amino-C₁-C₄-alkyl-carbonyl    -   (R⁵)₂N—C₃-C₇-cycloalkyl-    -   (R⁵)₂N—C₁-C₄-alkyl-    -   (R⁵)₂N—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   (R⁵)₂N—C₃-C₇-cycloalkyl-carbonyl-    -   R⁵O—C₃-C₇-cycloalkyl-    -   R⁵O—C₁-C₄-alkyl-    -   R⁵O—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   R⁵O—(C₁-C₄-alkyl)-C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   R⁵O—(hydroxy-C₁-C₄-alkyl)-C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   (R⁵)₂N—CO—C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   C₁-C₄-alkoxycarbonyl-C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   hydroxycarbonyl-C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   amino-carbonyl-C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   R⁵O—C₃-C₇-cycloalkyl-carbonyl-    -   (R⁵)₂N-carbonyl-C₁-C₄-alkyl-    -   R⁵O-carbonyl-C₁-C₄-alkyl-    -   aryl-C₁-C₄-alkyl-    -   heterocyclyl-C₁-C₄-alkyl-    -   C₁-C₄-alkyl-carbonyl-    -   halo-C₁-C₄-alkyl-carbonyl-    -   heterocyclyl-carbonyl-    -   aryl-carbonyl-    -   C₃-C₇-cycloalkyl-carbonyl-    -   C₃-C₇-cycloalkyl-C₁-C₄-alkyl-    -   heterocyclyl-    -   aryl-        -   wherein aryl, heterocyclyl and C₃-C₇-cycloalkyl are            unsubstituted or substituted by 1-4 substituents selected            from        -   halogen-        -   C₁-C₄-alkyl-        -   halo-C₁-C₄-alkyl-        -   C₁-C₄-alkyl-carbonyl-        -   C₃-C₇-cycloalkyl-carbonyl-        -   C₁-C₄-alkyl-sulfonyl-        -   amino-sulfonyl-        -   N—C₁-C₄-alkyl-amino-sulfonyl-        -   N,N-di-C₁-C₄-alkyl-amino-sulfonyl-        -   amino-carbonyl-        -   N—C₁-C₄-alkyl-amino-carbonyl-        -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-        -   oxo=    -   or    -   two R³, together with the N to which they are attached my form a        3, 4, 5, 6 or 7 membered heterocyclic ring, optionally        containing 1, 2, 3 or 4 additional N heteroatoms and optionally        containing a O atom and/or a S atom, said heterocyclic ring        being unsubstituted or substituted by 1, 2 or 3 substituents        selected from:    -   halogen-    -   hydroxy-C₁-C₄-alkyl-    -   C₁-C₄-alkyl-    -   halo-C₁-C₄-alkyl-    -   oxo=    -   hydroxy-    -   C₁-C₄-alkoxy-    -   amino-    -   N—C₁-C₄-alkyl-amino-    -   N,N-di-C₁-C₄-alkyl-amino-    -   hydroxy-carbonyl-    -   C₁-C₄-alkoxy-carbonyl-    -   amino-carbonyl-    -   N—C₁-C₄-alkyl-amino-carbonyl-    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-    -   C₁-C₄-alkyl-carbonyl-    -   C₁-C₄-alkyl-sulphonyl-    -   heterocyclyl-    -   C₁-C₄-alkyl-carbonyl-amino-    -   C₁-C₄-alkyl-carbonyl-N—C₁-C₄-alkyl-amino-;    -   and        each R⁵ is independently selected from:    -   H—    -   C₁-C₄-alkyl-    -   hydroxy-C₁-C₄-alkyl-    -   C₁-C₄-alkyl-carbonyl-    -   C₁-C₄-alkoxy-carbonyl-C₁-C₄-alkyl-    -   amino-carbonyl-C₁-C₄-alkyl-    -   N—C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-    -   C₁-C₄-alkyl-sulfonyl-    -   amino-sulfonyl-    -   N—C₁-C₄-alkyl-amino-sulfonyl-    -   N,N-di-C₁-C₄-alkyl-amino-sulfonyl-    -   heterocyclyl-carbonyl-    -   amino-carbonyl-    -   N—C₁-C₄-alkyl-amino-carbonyl-    -   N,N-di-C₁-C₄-alkyl-amino-carbonyl-    -   C₃-C₇-cycloalkyl-carbonyl-    -   C₁-C₄-alkoxy-carbonyl-amino-C₁-C₄-alkyl-    -   C₁-C₄-alkoxy-carbonyl-N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-    -   C₁-C₄-alkoxy-carbonyl-    -   C₃-C₇-cycloalkyl-    -   hydroxy-C₃-C₇-cycloalkyl-    -   or    -   two R⁵, together with the N to which they are attached may form        a 3, 4, 5, 6 or 7 membered heterocyclic ring, optionally        containing 1, 2, 3 or 4 additional N heteroatoms and/or        optionally containing a O atom and/or a S atom, said        heterocyclic ring being unsubstituted or substituted by from 1,        2 or 3 substituents independently selected from    -   C₁-C₄-alkyl-    -   oxo=,    -   C₁-C₄-alkyl-carbonyl,    -   C₁-C₄-alkyl-sulphonyl,    -   hydroxy-C₁-C₄-alkyl;    -   with the proviso that if Z is CH₂, n is 0 or 1, so that when n        is 1 then R¹ is ortho-    -   chloro, and R² is selected from    -   para-C₁-C₃-alkyl-phenyl-    -   para-(halo-C₁-C₃-alkyl)-phenyl-    -   para-C₁-C₃-alkoxy-phenyl-    -   para-halo-phenyl-    -   para-nitro-phenyl-    -   para-(C₁-C₃-alkoxy-carbonyl)-phenyl-    -   para-(hydroxy-carbonyl)-phenyl-    -   wherein the phenyl is optionally substituted by 1-2 additional        substituents, said substituents being independently selected        from halo and methyl,    -   then R⁶ and R⁷ are not both ethoxy or methoxy.        10. A compound of formula (I) as described in embodiment 9,        wherein

R⁶ is selected from H, hydroxy, methoxy, ethoxy, propoxy (isopropoxy orn-propoxy), butoxy (preferably isobutoxy), morpholin-4-ylethoxy,aminoethoxy, 4-methylpiperazin-1-ylcarbonylmethoxy, dimethylaminoethoxy,dimethylaminopropoxy, hydroxyethoxy, hydroxypropoxy,dimethylaminocarbonylmethoxy, methylaminocarbonylmethoxy and d₃ methoxy,and preferably R⁶ is methoxy;

R⁷ is selected from methoxy, ethoxy, butoxy (including isobutoxy,sec-butoxy, (R)-sec-butoxy, (S)-sec-butoxy), propoxy (includingisopropoxy, n-propoxy), cyclopropylmethoxy, cyclopentyloxy,morpholinyl-4-ylpropoxy, 3-hydroxypropoxy, 3-dimethylaminopropoxy,1-ethylpropoxy, 3-aminopropoxy, cyclobutoxy, 1-methylbutoxy,1,2-dimethylpropoxy, 3-amino-1-methyl-propoxy, cyclohexyloxy, benzyloxy,cyclohexylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy,2-methoxy-1-methyl-ethoxy (including in particular (R)2-methoxy-1-methyl-ethoxy), 1,3-dimethyl-but-3-enyloxy,1-methyl-but-3-enyloxy, pyridin-4-ylmethoxy, trifluoromethoxy,methoxyethoxy, (R) tetrahydrofuran-2-ylmethoxy, (S)tetrahydrofuran-2-ylmethoxy, (R)-2-methoxy-propoxy,2-methoxy-1-methyl-ethoxy, 1-hydroxy-cyclopropylmethoxy,3-methoxy-propoxy, oxetan-2-ylmethoxy, 2,2-difluoro-ethoxy,isopropylamino, ethylcarbonylamino, isopropyl-propyl-amino,(dimethylaminoethyl)-isopropyl-amino,(methylcarbonylaminoethyl)isopropylamino, isobutylamino,cyclopentylmethylamino, 1-ethyl-propyl-amino, cyclohexylamino,butylamino (including sec-butylamino), cyclobutylamino,cyclopentylamino, propylamino, ethylamino, benzylamino,cyclopropylmethylamino, cyclohexylmethylamino, methylcarbonylamino,isopropylcarbonylamino, (methylcarbonyl)isopropylamino,(ethylcarbonyl)isopropylamino, (isopropyl)methyl-amino and(isopropyl)ethyl-amino, and preferably R⁷ is isopropoxy;

n is 0 or 1;

R¹ is selected from hydrogen, fluoro, chloro, methyl, methoxy, bromo,nitro, amino, amino-carbonyl-amino-, methylaminocarbonylamino-,methylaminocarbonyl-, methylcarbonylamino-, ethylaminocarbonylamino-,ethylcarbonylamino-, (ethyl)methylamino-, dimethylamino-,aminocarbonyl-, hydroxymethyl-, aminomethyl-,methylcarbonylaminomethyl-, methylaminomethyl;

R² is selected from:

-   -   (A) i phenyl substituted by:

4-dimethylamino-, 4-methylamino-, 4-morpholin-4-yl-, 4-pyrrolidin-1-yl-,4-dimethylamino-2-methoxy, 2-methoxy-4-methyl-,2-methoxy-4-morpholin-4-yl-, 4-dimethylamino-2-methoxy-,4-dimethylamino-2-methyl-, 4-(N-methyl-N-pyridin-4-ylmethyl-amino)-,4-(2-oxo-pyrrolidin-1-yl), 4-pyrazol-1-yl-, 4-methylcarbonylamino-,4-(2-oxo-azetidin-1-yl)-, 4-(N-methyl-N-ethyl-amino)carbonyl-,4-(piperidine-1-carbonyl), 4-methylaminocarbonyl,4-diethylaminocarbonyl-, 4-dimethylaminocarbonyl,4-(pyrrolidine-1-carbonyl)-, 4-aminocarbonyl-,4-(N-methyl-N-pyridin-4-yl-aminocarbonyl)-,4-(N-pyridin-4-yl-aminocarbonyl)-, 4-(N-pyridin-3-yl-aminocarbonyl)-,4-hydroxymethyl, 4-N-methylcarbonyl-N-methyl-amino-,4-(N-methylcarbonyl-N-cyclopentylmethyl-amino)-,4-(N-methyl-N-piperidin-3-yl-methyl-amino)-,4-[methyl-(1-methyl-piperidin-3-ylmethyl)-amino]-,4-(N-methyl-N-piperidin-4-ylmethyl-amino)-,4-[(1-Acetyl-piperidin-4-ylmethyl)-methyl-amino]-,4-[(1-methanesulfonyl-piperidin-4-ylmethyl)-methyl-amino]-,4-[(4-Amino-cyclohexylmethyl)-methyl-amino]-,4-[(4-ethylamino-cyclohexylmethyl)-methyl-amino]-,4-{[4-(ethyl-methyl-amino)-cyclohexylmethyl]-methyl-amino}-,4-diethylamino, 4-(N-cyclopentylmethyl-N-methyl-amino)-,4-(N-isopropyl-N-methyl-amino)-, 4-(N-cyclopentyl-N-methyl-amino)-,4-(N-cyclohexyl-N-methyl-amino)-, 4-(N-sec-butyl-N-methyl-amino)-,4-(N-cyclopropylmethyl-N-methyl-amino)-,4-(N-cyclohexylmethyl-N-methyl-amino)-, 4-(N-isobutyl-N-methyl-amino)-,4-(N-Benzyl-N-methyl-amino)-, 4-(N-ethyl-N-methyl-amino)-,4-ethylamino-, 4-dipropylamino-, 4-(N-cyclobutyl-N-methyl-amino)-,4-[(2-fluoro-benzyl)-methyl-amino]-,4-[(2,3-difluoro-benzyl)-methyl-amino]-,4-[methyl-(3-trifluoromethyl-benzyl)-amino]-,4-[methyl-(4-trifluoromethyl-benzyl)-amino]-,4-[(3-fluoro-benzyl)-methyl-amino]-,4-(N-methyl-N-pyridin-3-ylmethyl-amino)-,4-[(4-fluoro-benzyl)-methyl-amino]-,4-[(3,4-difluoro-benzyl)-methyl-amino]-,4-[(pyridin-4-ylmethyl)-amino]-,4-(N-cyclopropylmethyl-N-pyridin-4-ylmethyl-amino)-,4-(N-ethyl-N-pyridin-4-ylmethyl-amino)-,4-[(2-morpholin-4-yl-ethyl)-pyridin-4-ylmethyl-amino]-,4-(N-methyl-N-pyrimidin-4-ylmethyl-amino)-,4-[(3-fluoro-pyridin-4-ylmethyl)-methyl-amino]-,4-(N-methyl-N-thiophen-3-ylmethyl-amino)-,4-[methyl-(3-methyl-3H-imidazol-4-ylmethyl)-amino]-,4-(N-furan-3-ylmethyl-N-methyl-amino)-,4-[methyl-(2-morpholin-4-yl-ethyl)-amino]-,4-[methyl-(1-methyl-piperidin-4-ylmethyl)-amino]-,4-[methyl-(4-propylamino-cyclohexylmethyl)-amino]-,4-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-,4-[(4-amino-cyclohexylmethyl)-methyl-amino]-,4-[(4-dimethylamino-cyclohexylmethyl)-ethyl-amino]-,4-[methyl-(4-pyrrolidin-1-yl-cyclohexylmethyl)-amino]-,4-[methyl-(4-piperidin-1-yl-cyclohexylmethyl)-amino]-,[4-(methyl-piperidin-4-ylmethyl-amino)-,4-{methyl-[4-(3-methyl-4-oxo-imidazolidin-1-yl)-cyclohexylmethyl]-amino}-,4-(3-amino-1H-pyrazol-4-yl)-, 4-(3-Amino-5-methyl-1H-pyrazol-4-yl)-,4-(3,5-dimethyl-1H-pyrazol-4-yl)-, 4-(1-pyrrolidin-1-yl-ethyl]-,4-(1-morpholin-4-yl-ethyl)-, 4-(1-hydroxy-ethyl)-,4-[1-(piperidin-4-ylamino)-ethyl],4-[1-(N-piperidin-4-yl-N-methylcarbonyl-amino)ethyl],4-[1-(N-methyl-N-piperidin-4-yl-amino)-ethyl]-,4-{1-[(4-dimethylamino-cyclohexyl)-methyl-amino]ethyl}-,4-[1-(4-amino-cyclohexylamino)-ethyl]-,4-[1-(4-dimethylamino-piperidin-1-yl)-ethyl]-,4-{1-[4-(isopropyl-methyl-amino)-piperidin-1-yl]-ethyl}-,4-(1-dimethylamino-ethyl)-, 4-[1-(4-hydroxy-piperidin-1-yl)-ethyl],4-[1-(2-dimethylamino-ethylamino)-ethyl]-,4-[1-((R)-3-hydroxy-pyrrolidin-1-yl)-ethyl],4-[1-((S)-3-hydroxy-pyrrolidin-1-yl)-ethyl],4-[1-((S)-3-hydroxy-piperidin-1-yl)-ethyl],4-[1-((R)-3-hydroxy-piperidin-1-yl)-ethyl],4-(1-thiomorpholin-4-yl-ethyl)-,4-(1-N-isobutyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-propyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-isopropyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclopropyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclohexylmethyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclopentyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclohexyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclopropylmethyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclopentylmethyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-benzyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-cyclobutyl-N-methylcarbonyl-amino-ethyl)-,4-(1-N-pyrrolidine-3-carbonyl-N-ethyl-amino-ethyl)-,4-(1-N-cis-4-amino-cyclohexanecarbonyl-N-ethyl-amino-ethyl)-,4-(1-N-trans-4-amino-cyclohexanecarbonyl-N-ethyl-amino-ethyl)-,4-(1-N-4-dimethylamino-cyclohexanecarbonyl-N-ethyl-amino-ethyl)-,4-(1-N-4-dimethylamino-cyclopentanecarbonyl-N-ethyl-amino-ethyl)-,4-(1-N-1-methyl-pyrrolidine-3-yl-carbonyl-N-ethyl-amino-ethyl)-,4-(1-N-4-dimethylamino-cyclohexanecarbonyl-N-ethyl-amino-ethyl)-,4-[1-(piperidin-3-ylamino)-ethyl],4-(1-N-(2-aminoethyl)-N-methylcarbonyl-amino-ethyl)-,4-(1-N-(2-dimethylaminoethyl)-N-methylcarbonyl-amino-ethyl)-,4-(1-N-(3-aminopropyl)-N-methylcarbonyl-amino-ethyl)-,4-(1-N-(3-dimethylaminopropyl)-N-methylcarbonyl-amino-ethyl)-,4-[1-(N-ethyl-N-piperidin-4-yl-amino)-ethyl]-,4-[1-(3-Amino-piperidin-1-yl)-ethyl],4-[1-((R)-3-Amino-pyrrolidin-1-yl)-ethyl],4-[1-((S)-3-Amino-pyrrolidin-1-yl)-ethyl]-,4-[1-(3-dimethylamino-pyrrolidin-1-yl)-ethyl],[1-(4-diethylamino-piperidin-1-yl)-ethyl],4-O-(3-oxo-morpholin-4-yl)-ethyl),4-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-,4-(N-methyl-N-ethyl-amino-carbonyl)-,4-(N-cyclopropylmethyl-N-methyl-amino)-, 4-(2-oxo-azetidin-1-yl),4-(1-N-methylcarbonyl-N-ethyl-amino-ethyl),4-(morpholin-4-yl-cyclohexylmethyl)-amino)-,4-(morpholin-4-yl-cyclohexylmethyl)-methyl-amino)-,4-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-3-methyl-,4-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-3-fluoro-,4-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-2-methoxy-,4-[1-(4-Acetyl-piperazin-1-yl)-ethyl],4-[1-(4-dimethylamino-piperidin-1-yl)-ethyl]-,4-[(-4-dimethylamino-cyclohexylmethyl)-methyl-amino]-,4-[(-4-dimethylamino-cyclohexylmethyl)-ethyl-amino]-,4-[2-(4-dimethylamino-piperidin-1-yl)-1-methyl-ethyl],4-[2-(4-dimethylamino-piperidin-1-yl)-1-methyl-2-oxo-ethyl]-,4-imidazol-1-ylmethyl-, 4-(N-trifluoromethyl-carbonyl-N-methyl-amino)-,4-[1-(2-oxo-piperazin-1-yl)-ethyl]-,4-(2-hydroxy-ethyl)-2-oxo-piperazin-1-yl]-ethyl]-,4-[1-(methylcarbonylamino)-ethyl]-,4-[1-(methoxymethylcarbonylamino)-ethyl],4-[1-(dimethylamino-methyl-carbonylamino)-ethyl],4-(2-oxo-pyrrolidin-1-yl), 4-(2-oxo-imidazolidin-1-yl)- or4-(3-amino-5-ethyl-1H-pyrazol-4-yl)-, or

R² is selected from phenyl substituted by:

2-fluoro or 3-fluoro and substituted in the para position (relative tothe isoquinolinone or quinazolinone), by:

or R² is selected from phenyl substituted in the ortho position(relative to the isoquinolinone or quinazolinone), by methoxy andsubstituted in the para position (relative to the isoquinolinone orquinazolinone), by:

or R² is phenyl substituted in the para position (relative to theisoquinolinone or quinazolinone), by:

-   -   (A) ii or R² is 2-pyridyl (relative to the isoquinolinone or        quinazolinone), substituted by:        5-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]-,        5-[(4-amino-cyclohexylmethyl)amino]-,

-   -   (A) iii or R² is 3-pyridyl (relative to the isoquinolinone or        quinazolinone), substituted by:

-   6-[(4-dimethylamino-cyclohexylmethyl)-methyl-amino]- or    6-[(3-hydroxy-cyclobutylmethyl)-methyl-amino]-,

-   or R² is 3-pyridyl (relative to the isoquinolinone or    quinazolinone), substituted in the 6 position by:    6-{methyl-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylmethyl]-amino}-,    6-{methyl-[4-(2-oxo-imidazolidin-1-yl)-cyclohexylmethyl]-amino}-,

or R² is 3-pyridyl (relative to the isoquinolinone or quinazolinone),substituted by: 2 fluoro-6-

-   -   (B) i or R² is phenyl substituted by:        -   4-methoxy, 4-cyano, 3,4-dimethyl, 2,4-dimethyl,            4-methoxy-2-methyl-, 2-chloro-4-methyl-, 2,4-dimethoxy-,            3,4-dichloro-, 4-methyl-, 3,4-dimethoxy,            2-methoxy-4-methyl-, 4-(1H-pyrazol-4-yl)-,            4-(3,5-dimethyl-1H-pyrazol-4-yl)-,

-   -   (B) ii or R² is 2-pyridyl (relative to the isoquinolinone or        quinazolinone), substituted by 4-methyl,    -   (B) iii or R² is 3-pyridyl (relative to the isoquinolinone or        quinazolinone), substituted by 4-methyl,    -   (C) or R² is phenyl substituted by:        -   4-methyl-2-(3-morpholin-4-yl-propoxy)-,            4-methyl-2-hydroxycarbonylmethoxy-, 2-methoxy-5-methyl-,            4-methyl-2-(2H-tetrazol-5-ylmethoxy)-,            4-methyl-2-(thiazol-5-ylmethoxy)-,            4-methoxycarbonyl-2-tetrazol-5-ylmethoxy,            4-methoxycarbonyl-2 methoxy,            4-methoxycarbonyl-2-thiazol-5-ylmethoxy)-,            4-methyl-2-(2-morpholin-4-yl-ethoxy),            2-(3-dimethylamino-propoxy)-4-methyl-,            4-methyl-2-[2-(4-methyl-piperazin-1-yl)ethoxy]-,            4-methyl-2-[3-(4-methyl-piperazin-1-yl)-propoxy]-,            2-methoxycarbonylmethoxy-5-chloro-,            2-hydroxycarbonylmethoxy-5-chloro-,            5-chloro-2-(2-dimethylamino-ethoxy)-,            5-chloro-2-(3-morpholin-4-yl-propoxy)-,            5-chloro-2-(2-morpholin-4-yl-ethoxy)-,            5-chloro-2-(3-dimethylamino-propoxy)-,            5-chloro-2-(3-hydroxy-propoxy)- or            5-chloro-2-(2-hydroxy-ethoxy)-,    -   (D) or R² is (C-bound)-heterocycle selected from benzofuran-5-yl        and 1-methyl-1H-indazol-5-yl,    -   (E) or R² is pyrazin-2-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 5 position by:

-   -   (F) or R² is pyridazin-3-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 6 Position by:

-   -   (G) or R² is pyrimidin-2-yl (relative to the isoquinolinone or        quinazolinone), substituted at the 5 position by:

The invention claimed is:
 1. A compound of formula (I), orpharmaceutically acceptable salt thereof,

wherein Z is CH₂; X is halogen; R⁶ is independently selected from thegroup consisting of H— R′O— (R′)₂N—; R⁷ is independently selected fromthe group consisting of R′O— (R′)₂N—; each R′ is independently selectedfrom the group consisting of H— C₁-C₇-alkyl- C₁-C₇-alkenyl-halo-C₁-C₇-alkyl- halo-C₁-C₇-alkenyl- C₃-C₁₂-cycloalkyl- heterocyclyl-aryl- hydroxy-C₁-C₇-alkyl- C₁-C₇-alkoxy-C₁-C₇-alkyl- amino-C₁-C₇-alkyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl- N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl- heterocyclyl-C₁-C₇-alkyl-aryl-C₁-C₇-alkyl- C₁-C₇-alkyl-carbonyl- halo-C₁-C₇-alkyl-carbonyl-hydroxy-C₁-C₇-alkyl-carbonyl- C₁-C₇-alkoxy-C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-carbonyl- N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-C₃-C₁₂-cycloalkyl-carbonyl- heterocyclyl-C₁-C₇-alkyl-carbonyl-aryl-C₁-C₇-alkyl-carbonyl- C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-carbonyl-heterocyclyl-carbonyl- aryl-carbonyl- C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-halo-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-hydroxy-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-C₁-C₇-alkoxy-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl-C₃-C₁₂-cycloalkyl-carbonyl-C₁-C₇-alkyl-heterocyclyl-carbonyl-C₁-C₇-alkyl- aryl-carbonyl-C₁-C₇-alkyl-carbonyl-C₁-C₇-alkyl- hydroxy-carbonyl-C₁-C₇-alkyl-C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl- amino-carbonyl-C₁-C₇-alkyl-N—C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-N,N-di-C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-C₃-C₁₂-cycloalkyl-carbonyl-C₁-C₇-alkyl-heterocyclyl-carbonyl-C₁-C₇-alkyl- aryl-carbonyl-C₁-C₇-alkyl-C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-halo-C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-halo-C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl- wherein aryl,heterocyclyl and C₃-C₁₂-cycloalkyl are unsubstituted or substituted by1-4 substituents selected from C₁-C₇-alkyl, halo-C₁-C₇-alkyl, halogen,hydroxy, C₁-C₇-alkoxy, amino, nitro or cyano; each R¹ is independentlyselected from the group consisting of halogen- cyano- nitro-C₁-C₇-alkyl- C₁-C₇-alkenyl- halo-C₁-C₇-alkyl- hydroxy- C₁-C₇-alkoxy-amino- N—C₁-C₇-alkyl-amino- N,N-di-C₁-C₇-alkyl-amino-amino-carbonyl-amino- N—C₁-C₇-alkyl-amino-carbonyl-amino-N,N-di-C₁-C₇-alkyl-amino-carbonyl-amino- C₁-C₇-alkyl-carbonyl-amino-amino-carbonyl- N—C₁-C₇-alkyl-amino-carbonyl-N,N-di-C₁-C₇-alkyl-amino-carbonyl- hydroxy-C₁-C₇-alkyl-amino-C₁-C₇-alkyl- N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-N,N-di-C₁-C₇-alkyl-amino-C₁-C₇-alkyl-C₁-C₇-alkyl-carbonyl-amino-C₁-C₇-alkyl-C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-; n is 0 to 2; R²is selected from (A) phenyl, 2-pyridyl and 3-pyridyl substituted in thepara-position relative to the isoquinolinone or quinazolinone, by(R³)₂N—Y— wherein Y is absent (a bond) or (R³)₂N—Y— is selected from

and wherein said phenyl, 2-pyridyl or 3-pyridyl is optionallysubstituted by 1-2 additional substituents selected from halogen- cyano-C₁-C₇-alkyl- halo-C₁-C₇-alkyl- hydroxy- C₁-C₇-alkoxy- andhydroxy-C₁-C₇-alkyl-; or (B) phenyl, 2-pyridyl or 3-pyridyl substitutedin para-position relative to the isoquinolinone or quinazolinone by asubstituent selected from cyano- halogen- nitro- C₁-C₇-alkyl-halo-C₁-C₇-alkyl- hydroxy-C₁-C₇-alkyl- hydroxy-carbonyl-C₁-C₇-alkoxy-carbonyl- C₁-C₇-alkyl-carbonyl- C₁-C₇-alkoxy-(C-bound)-heterocyclyl- wherein (C-bound)-heterocyclyl is unsubstitutedor substituted by 1-4 substituents selected from C₁-C₇-alkyl,halo-C₁-C₇-alkyl, halogen, hydroxy, C₁-C₇-alkoxy, amino, nitro or cyano;and optionally substituted by 1-2 additional substituents selected fromhalogen- cyano- C₁-C₇-alkyl- halo-C₁-C₇-alkyl- hydroxy- C₁-C₇-alkoxy-(C-bound or N-bound)heterocyclyl-C₁-C₄-alkyl- hydroxy-C₁-C₇-alkyl-; or(C) phenyl, substituted in ortho-position relative to the isoquinolinoneor quinazolinone by R³O— and substituted in para- or meta-position by asubstituent selected from methyl, chloro, C₁-C₇-alkyl-carbonyl- orC₁-C₇-alkoxy-carbonyl-; (D) (C-bound)-heterocycle selected from

wherein Z is a 4-6 membered heterocyclic ring, annulated to phenyl inpara and meta position, containing 1-3 heteroatoms selected from N, O orS, which is optionally substituted by 1-2 additional substituentsselected from halogen- cyano- C₁-C₇-alkyl- halo-C₁-C₇-alkyl- hydroxy-C₁-C₇-alkoxy- hydroxy-C₁-C₇-alkyl-; (E) pyrazin-2-yl, substituted at the5 position by:

(F) pyridazin-3-yl, substituted at the 6 position by:

(G) pyrimidin-2-yl, substituted at the 5 position by:

wherein each R³ is independently selected from H— C₁-C₇-alkyl-hydroxy-C₁-C₇-alkyl- C₃-C₁₂-cycloalkyl-C₁-C₇-alkoxy-C₁-C₇-alkyl-carbonyl- amino-C₁-C₇-alkyl-carbonylN—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl N,N-diC₁-C₇-alkyl-amino-C₁-C₇-alkyl-carbonyl (R⁵)₂N—C₃-C₁₂-cycloalkyl-(R⁵)₂N—C₁-C₇-alkyl- (R⁵)₂N—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-(R⁵)₂N—C₃-C₁₂-cycloalkyl-carbonyl- R⁵O—C₃-C₁₂-cycloalkyl-R⁵O—C₁-C₇-alkyl- R⁵O—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-R⁵O—(C₁-C₇-alkyl)-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-R⁵O—(hydroxy-C₁-C₇-alkyl)-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-(R⁵)₂N—CO—C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-C₁-C₇-alkoxycarbonyl-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-hydroxycarbonyl-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-amino-carbonyl-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl-R⁵O—C₃-C₁₂-cycloalkyl-carbonyl- (R⁵)₂N-carbonyl-C₁-C₇-alkyl-R⁵O-carbonyl-C₁-C₇-alkyl- aryl-C₁-C₇-alkyl- heterocyclyl-C₁-C₇-alkyl-C₁-C₇-alkyl-carbonyl- halo-C₁-C₇-alkyl-carbonyl- heterocyclyl-carbonyl-aryl-carbonyl- C₃-C₁₂-cycloalkyl-carbonyl-C₃-C₁₂-cycloalkyl-C₁-C₇-alkyl- heterocyclyl- aryl- wherein aryl,heterocyclyl and C₃-C₁₂-cycloalkyl are unsubstituted or substituted by1-4 substituents selected from halogen- C₁-C₇-alkyl- halo-C₁-C₇-alkyl-C₁-C₇-alkyl-carbonyl- C₃-C₁₂-cycloalkyl-carbonyl- C₁-C₇-alkyl-sulfonyl-amino-sulfonyl- N—C₁-C₇-alkyl-amino-sulfonyl-N,N-di-C₁-C₇-alkyl-amino-sulfonyl- amino-carbonyl-N—C₁-C₇-alkyl-amino-carbonyl- N,N-di-C₁-C₇-alkyl-amino-carbonyl- oxo= ortwo R³, together with the N to which they are attached my form a 3-9membered heterocyclic ring, optionally containing 1-4 additionalheteroatoms selected from N, O or S, said heterocyclic ring isunsubstituted or substituted by 1-3 substituents selected from: halogen-hydroxy-C₁-C₇-alkyl- C₁-C₇-alkyl- halo-C₁-C₇-alkyl- oxo= hydroxy-C₁-C₇-alkoxy- amino- N—C₁-C₇-alkyl-amino- N,N-di-C₁-C₇-alkyl-amino-hydroxy-carbonyl- C₁-C₇-alkoxy-carbonyl- amino-carbonyl-N—C₁-C₇-alkyl-amino-carbonyl- N,N-di-C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-carbonyl- C₁-C₇-alkyl-sulphonyl- heterocyclyl-C₁-C₇-alkyl-carbonyl-amino- C₁-C₇-alkyl-carbonyl-N—C₁-C₇-alkyl-amino-;and each R⁵ is independently selected from: H— C₁-C₇-alkyl-hydroxy-C₁-C₇-alkyl- C₁-C₇-alkyl-carbonyl-C₁-C₇-alkoxy-carbonyl-C₁-C₇-alkyl- amino-carbonyl-C₁-C₇-alkyl-N—C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl-N,N-di-C₁-C₇-alkyl-amino-carbonyl-C₁-C₇-alkyl- C₁-C₇-alkyl-sulfonyl-amino-sulfonyl- N—C₁-C₇-alkyl-amino-sulfonyl-N,N-di-C₁-C₇-alkyl-amino-sulfonyl- heterocyclyl-carbonyl-amino-carbonyl- N—C₁-C₇-alkyl-amino-carbonyl-N,N-di-C₁-C₇-alkyl-amino-carbonyl- C₃-C₁₂-cycloalkyl-carbonyl-C₁-C₇-alkoxy-carbonyl-amino-C₁-C₇-alkyl-C₁-C₇-alkoxy-carbonyl-N—C₁-C₇-alkyl-amino-C₁-C₇-alkyl-C₁-C₇-alkoxy-carbonyl- C₃-C₁₂-cycloalkyl- hydroxy-C₃-C₁₂-cycloalkyl- ortwo R⁵, together with the N to which they are attached my form a 3-9membered heterocyclic ring, optionally containing from 1-4 additionalheteroatoms selected from N, O or S, said heterocyclic ring isunsubstituted or substituted by from 1 to 3 substituents selected fromC₁-C₇-alkyl- oxo=, C₁-C₇-alkyl-carbonyl, C₁-C₇-alkyl-sulphonyl,hydroxy-C₁-C₇-alkyl; with the proviso that if Z is CH₂, n is 0 or 1, andwhen present, R¹ is ortho-chloro, and R² is selected frompara-C₁-C₃-alkyl-phenyl- para-(halo-C₁-C₃-alkyl)-phenyl-para-C₁-C₃-alkoxy-phenyl- para-halo-phenyl- para-nitro-phenyl-para-(C₁-C₃-alkoxy-carbonyl)-phenyl- para-(hydroxy-carbonyl)-phenyl-wherein the phenyl is optionally substituted by 1-2 additionalsubstituents, said substituents being independently selected from haloand methyl, then R⁶ and R⁷ are not both ethoxy or methoxy, aryl meansphenyl or naphthyl, and heterocyclyl means an unsaturated, saturated, orpartially saturated ring or ring system comprising 3, 4, 5, 6, 7, 8, 9,10, 11 or 12 ring atoms, and containing at least one heteroatom selectedfrom N, O and S, where the N and S can also optionally be oxidized, andwherein, unless otherwise stated, the heterocyclic group can be attachedat a heteroatom or a carbon atom.
 2. A compound of formula (I), orpharmaceutically acceptable salt thereof, as claimed in claim 1, whereinX is chloro.
 3. A compound of formula (I), or pharmaceuticallyacceptable salt thereof, according to claim 1, wherein each R′ isindependently selected from H— C₁-C₆-alkyl- heterocyclyl-C₁-C₄-alkyl-amino-C₁-C₄-alkyl- N—C₁-C₄-alkyl-amino-C₁-C₄-alkyl-N,N-di-C₁-C₄-alkyl-amino-C₁-C₄-alkyl- heterocyclyl-carbonyl-C₁-C₄-alkyl-hydroxy-C₁-C₄-alkyl- amino-carbonyl-C₁-C₄-alkyl-N—C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl-N,N-di-C₁-C₄-alkyl-amino-carbonyl-C₁-C₄-alkyl- d₃ methoxy,C₃-C₇-cycloalkyl-C₁-C₄-alkyl- C₃-C₇-cycloalkyl- aryl-C₁-C₄-alkyl-C₁-C₄-alkoxy-C₁-C₄-alkyl- C₁-C₆-alkenyl- halo-C₁-C₄-alkyl-halo-C₁-C₄-alkenyl- C₁-C₄-alkyl-carbonyl-C₁-C₄-alkyl-carbonyl-amino-C₁-C₄-alkyl- aryl-C₁-C₄-alkyl- heterocyclyl-and aryl- wherein said C₃-C₇-cycloalkyl (including the C₃-C₇-cycloalkylsubstituent within C₃-C₇-cycloalkyl-C₁-C₄-alkyl-), is optionallysubstituted by hydroxy or methyl, and wherein aryl (including withinaryl-C₁-C₄-alkyl-), and heterocyclyl (including withinheterocyclyl-C₁-C₄-alkyl- and heterocyclyl-carbonyl-C₁-C₄-alkyl-), isoptionally substituted by 1 or 2 C₁-C₄-alkyl substituents.
 4. A compoundof formula (I), or pharmaceutically acceptable salt thereof, as claimedin claim 1, wherein R⁶ is R′O—.
 5. A compound of formula (I), orpharmaceutically acceptable salt thereof, as claimed in claim 1, whereinR² is R′O—.
 6. A compound of formula (I), or pharmaceutically acceptablesalt thereof, as claimed in claim 1, wherein R² is selected from: (A)phenyl, 2-pyridyl or 3-pyridyl substituted in para-position relative tothe isoquinolinone or quinazolinone by (R³)₂N—Y— wherein Y is absent (abond) or (R³)₂N—Y— is selected from

and wherein said phenyl, 2-pyridyl or 3-pyridyl are optionallysubstituted by 1-2 additional substituents selected from halogen- cyano-C₁-C₄-alkyl- halo-C₁-C₄-alkyl- hydroxy- C₁-C₄-alkoxy-hydroxy-C₁-C₄-alkyl-.
 7. A compound of formula (I), or pharmaceuticallyacceptable salt thereof, as claimed in claim 6, wherein R² is selectedfrom: (A) phenyl, 2-pyridyl or 3-pyridyl, substituted in para-positionrelative to the isoquinolinone or quinazolinone by (R³)₂N—Y—, wherein Yis absent (a bond), and wherein the phenyl, 2-pyridyl or 3-pyridyl arenot further substituted.
 8. A compound of formula (I), or apharmaceutically acceptable salt thereof, as claimed in claim 1, whereineach R³ is independently selected from: C₁-C₄-alkyl-C₃-C₂-cycloalkyl-C₁-C₄-alkyl- heterocyclyl-C₁-C₄-alkyl-aryl-C₁-C₄-alkyl- (R⁵)₂N—C₃-C₂-cycloalkyl-(R⁵)₂N—C₃-C₂-cycloalkyl-C₁-C₄-alkyl-(R⁵)₂N—CO—C₃-C₂-cycloalkyl-C₁-C₄-alkyl- aryl- heterocyclyl-C₃-C₂-cycloalkyl- wherein aryl, heterocyclyl and C₃-C₇-cycloalkyl areunsubstituted or substituted by 1-4 substituents selected from halogen-C₁-C₄-alkyl- halo-C₁-C₄-alkyl- C₁-C₄-alkyl-carbonyl-C₃-C₂-cycloalkyl-carbonyl- C₁-C₄-alkyl-sulfonyl- amino-sulfonyl-N—C₁-C₄-alkyl-amino-sulfonyl- N,N-di-C₁-C₄-alkyl-amino-sulfonyl-amino-carbonyl- N—C₁-C₄-alkyl-amino-carbonyl-N,N-di-C₁-C₄-alkyl-amino-carbonyl- and oxo=.
 9. A compound of formula(I), or a pharmaceutically acceptable salt thereof, as claimed in claim1, wherein R² is selected from (A) phenyl, 2-pyridyl or 3-pyridyl,substituted in para-position by (R³)₂N—Y—, wherein Y is absent, andwherein one R³ is C₁-C₄-alkyl-, and the other R³ is(R⁵)₂N-cyclohexyl-C₁-C₂-alkyl-, and wherein the two R⁵, together withthe N to which they are attached form a 6 membered heterocyclic ring,optionally containing 1 additional N heteroatom and/or optionallycontaining an O atom and/or a S atom, said heterocyclic ring beingunsubstituted or substituted by 1 or 2 substituents independentlyselected from C₁-C₄-alkyl-, oxo=, C₁-C₄-alkyl-carbonyl,C₁-C₄-alkyl-sulphonyl, and hydroxy-C₁-C₄-alkyl.
 10. A compound offormula (I), or a pharmaceutically acceptable salt thereof, as claimedin claim 1, wherein when two R³ substituents are present, and they donot join to form a ring, at least one R³ substituent is C₁-C₄-alkyl-.11. A compound of the formula (I) as claimed in claim 1, in combinationwith one or more therapeutically active agents.
 12. A compound that is(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-oneor a pharmaceutically acceptable salt thereof.
 13. A compound, or apharmaceutically acceptable salt thereof, selected from:


14. A crystalline form I of(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino]-phenyl)-1,4-dihydro-2H-isoquinolin-3-onesulphate salt having a powder X ray diffraction pattern using Cu Kαradiation which includes the following peaks: Angle 2-Theta °: 18.8,21.3 and 22.7, error +/−0.2°.
 15. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(I) as defined in claim 1, and one or more pharmaceutically acceptablecarriers.